Multifactor dimensionality reduction (MDR) was developed as a nonparametric and model-free data mining method for detecting, characterizing, and interpreting epistasis in the absence of significant main effects in genetic and epidemiologic studies of complex traits such as disease susceptibility. The goal of MDR is to change the representation of the data using a constructive induction algorithm to make nonadditive interactions easier to detect using any classification method such as naïve Bayes or logistic regression. Traditionally, MDR constructed variables have been evaluated with a naïve Bayes classifier that is combined with 10-fold cross validation to obtain an estimate of predictive accuracy or generalizability of epistasis models. Traditionally, we have used permutation testing to statistically evaluate the significance of models obtained through MDR. The advantage of permutation testing is that it controls for false positives due to multiple testing. The disadvantage is that permutation testing is computationally expensive. This is an important issue that arises in the context of detecting epistasis on a genome-wide scale. The goal of the present study was to develop and evaluate several alternatives to large-scale permutation testing for assessing the statistical significance of MDR models. Using data simulated from 70 different epistasis models, we compared the power and type I error rate of MDR using a 1,000-fold permutation test with hypothesis testing using an extreme value distribution (EVD). We find that this new hypothesis testing method provides a reasonable alternative to the computationally expensive 1,000-fold permutation test and is 50 times faster. We then demonstrate this new method by applying it to a genetic epidemiology study of bladder cancer susceptibility that was previously analyzed using MDR and assessed using a 1,000-fold permutation test.

Motivation: Epistasis, the presence of gene–gene interactions, has been hypothesized to be at the root of many common human diseases, but current genome-wide association studies largely ignore its role. Multifactor dimensionality reduction (MDR) is a powerful model-free method for detecting epistatic relationships between genes, but computational costs have made its application to genome-wide data difficult. Graphics processing units (GPUs), the hardware responsible for rendering computer games, are powerful parallel processors. Using GPUs to run MDR on a genome-wide dataset allows for statistically rigorous testing of epistasis. Results: The implementation of MDR for GPUs (MDRGPU) includes core features of the widely used Java software package, MDR. This GPU implementation allows for large-scale analysis of epistasis at a dramatically lower cost than the standard CPU-based implementations. As a proof-of-concept, we applied this software to a genome-wide study of sporadic amyotrophic lateral sclerosis (ALS). We discovered a statistically significant two-SNP classifier and subsequently replicated the significance of these two SNPs in an independent study of ALS. MDRGPU makes the large-scale analysis of epistasis tractable and opens the door to statistically rigorous testing of interactions in genome-wide datasets. Availability: MDRGPU is open source and available free of charge from http://www.sourceforge.net/projects/mdr. Contact: jason.h.moore@dartmouth.edu Supplementary information: Supplementary data are available at Bioinformatics online. PMID:20081222

Epistasis, the presence of gene-gene interactions, has been hypothesized to be at the root of many common human diseases, but current genome-wide association studies largely ignore its role. Multifactor dimensionality reduction (MDR) is a powerful model-free method for detecting epistatic relationships between genes, but computational costs have made its application to genome-wide data difficult. Graphics processing units (GPUs), the hardware responsible for rendering computer games, are powerful parallel processors. Using GPUs to run MDR on a genome-wide dataset allows for statistically rigorous testing of epistasis. The implementation of MDR for GPUs (MDRGPU) includes core features of the widely used Java software package, MDR. This GPU implementation allows for large-scale analysis of epistasis at a dramatically lower cost than the standard CPU-based implementations. As a proof-of-concept, we applied this software to a genome-wide study of sporadic amyotrophic lateral sclerosis (ALS). We discovered a statistically significant two-SNP classifier and subsequently replicated the significance of these two SNPs in an independent study of ALS. MDRGPU makes the large-scale analysis of epistasis tractable and opens the door to statistically rigorous testing of interactions in genome-wide datasets. MDRGPU is open source and available free of charge from http://www.sourceforge.net/projects/mdr.

Applying a statistical method implies identifying underlying (model) assumptions and checking their validity in the particular context. One of these contexts is association modeling for epistasis detection. Here, depending on the technique used, violation of model assumptions may result in increased type I error, power loss, or biased parameter estimates. Remedial measures for violated underlying conditions or assumptions include data transformation or selecting a more relaxed modeling or testing strategy. Model-Based Multifactor Dimensionality Reduction (MB-MDR) for epistasis detection relies on association testing between a trait and a factor consisting of multilocus genotype information. For quantitative traits, the framework is essentially Analysis of Variance (ANOVA) that decomposes the variability in the trait amongst the different factors. In this study, we assess through simulations, the cumulative effect of deviations from normality and homoscedasticity on the overall performance of quantitative Model-Based Multifactor Dimensionality Reduction (MB-MDR) to detect 2-locus epistasis signals in the absence of main effects. Our simulation study focuses on pure epistasis models with varying degrees of genetic influence on a quantitative trait. Conditional on a multilocus genotype, we consider quantitative trait distributions that are normal, chi-square or Student's t with constant or non-constant phenotypic variances. All data are analyzed with MB-MDR using the built-in Student's t-test for association, as well as a novel MB-MDR implementation based on Welch's t-test. Traits are either left untransformed or are transformed into new traits via logarithmic, standardization or rank-based transformations, prior to MB-MDR modeling. Our simulation results show that MB-MDR controls type I error and false positive rates irrespective of the association test considered. Empirically-based MB-MDR power estimates for MB-MDR with Welch's t-tests are generally lower than those

Conclusions about the genetic architecture of a phenotype relating to the contributions of genetic additivity, dominance, epistasis or genotype × environment interaction, depend upon the statistical and distributional properties of the measured trait. This dependence is frequently ignored in contemporary genetic studies and can radically change the conclusions that may be drawn from the data. The interdependence of the conclusions about genetic architecture and instruments used for behavioral measurement is explored by simulated studies of the interaction between candidate genes and measured environment in psychiatric genetics. Trait values are simulated (N = 100,000) under several commonly encountered scenarios and subjected to two simulated 20-item psychological tests each comprising items with different patterns of difficulty and sensitivity to variation (discriminating power) in the latent trait. Test scores are generated for each test by summing the binary responses across all items. The full model for digenic additive and non-additive genetic effects and G × E is fitted to the trait values and test scores under a range of different simulated genetic architectures. Untransformed test scores show complex patterns of epistasis and G × E even when the underlying effects of genes and environment are purely additive and the transformation of symptom counts does not fully recover the simulated underlying genetic architecture. Accordingly, failing to allow for the theory of measurement when analyzing details of genetic architecture may frequently lead to replicable over-reporting of interactions and mislead potential investigators and funding agencies.

Linkage analysis is now being widely used to map markers on each chromosome in the human genome, to map genetic diseases, and to identify genetic forms of common diseases. Two-locus linkage analysis and multi-locus analysis have been investigated comprehensively, and many computer programs have been ...

Full Text Available Dissection of the genetic architecture of complex traits persists as a major challenge in biology; despite considerable efforts, much remains unclear including the role and importance of genetic interactions. This study provides empirical evidence for a strong and persistent contribution of both second- and third-order epistatic interactions to long-term selection response for body weight in two divergently selected chicken lines. We earlier reported a network of interacting loci with large effects on body weight in an F(2 intercross between these high- and low-body weight lines. Here, most pair-wise interactions in the network are replicated in an independent eight-generation advanced intercross line (AIL. The original report showed an important contribution of capacitating epistasis to growth, meaning that the genotype at a hub in the network releases the effects of one or several peripheral loci. After fine-mapping of the loci in the AIL, we show that these interactions were persistent over time. The replication of five of six originally reported epistatic loci, as well as the capacitating epistasis, provides strong empirical evidence that the originally observed epistasis is of biological importance and is a contributor in the genetic architecture of this population. The stability of genetic interaction mechanisms over time indicates a non-transient role of epistasis on phenotypic change. Third-order epistasis was for the first time examined in this study and was shown to make an important contribution to growth, which suggests that the genetic architecture of growth is more complex than can be explained by two-locus interactions only. Our results illustrate the importance of designing studies that facilitate exploration of epistasis in populations for obtaining a comprehensive understanding of the genetics underlying a complex trait.

High-order epistasis-where the effect of a mutation is determined by interactions with two or more other mutations-makes small, but detectable, contributions to genotype-fitness maps. While epistasis between pairs of mutations is known to be an important determinant of evolutionary trajectories, the evolutionary consequences of high-order epistasis remain poorly understood. To determine the effect of high-order epistasis on evolutionary trajectories, we computationally removed high-order epistasis from experimental genotype-fitness maps containing all binary combinations of five mutations. We then compared trajectories through maps both with and without high-order epistasis. We found that high-order epistasis strongly shapes the accessibility and probability of evolutionary trajectories. A closer analysis revealed that the magnitude of epistasis, not its order, predicts is effects on evolutionary trajectories. We further find that high-order epistasis makes it impossible to predict evolutionary trajectories from the individual and paired effects of mutations. We therefore conclude that high-order epistasis profoundly shapes evolutionary trajectories through genotype-fitness maps.

One of the major challenges in genetic linkage analyses is the study of complex diseases. The authors demonstrate here the use of two-locus linkage analysis in multiple sclerosis (MS), a multifactorial disease with a complex mode of inheritance. In a set of Finnish multiplex families, they have previously found evidence for linkage between MS susceptibility and two independent loci, the myelin basic protein gene (MBP) on chromosome 18 and the HLA complex on chromosome 6. This set of families provides a unique opportunity to perform linkage analysis conditional on two loci contributing to the disease. In the two-trait-locus/two-marker-locus analysis, the presence of another disease locus is parametrized and the analysis more appropriately treats information from the unaffected family member than single-disease-locus analysis. As exemplified here in MS, the two-locus analysis can be a powerful method for investigating susceptibility loci in complex traits, best suited for analysis of specific candidate genes, or for situations in which preliminary evidence for linkage already exists or is suggested. 41 refs., 6 tabs.

Determination of genetic basis of heterosis may promote hybrid production in Upland cotton (Gossypium hirsutum L.). This study was designed to explore the genetic mechanism of heterosis for yield and yield components in F2: 3 and F2: 4 populations derived from a hybrid ‘Xinza No. 1’. Replicated yield field trials of the progenies were conducted in 2008 and 2009. Phenotypic data analyses indicated overdominance in F1 for yield and yield components. Additive and dominance effects at single-locus level and digenic epistatic interactions at two-locus level were analyzed by 421 marker loci spanning 3814 cM of the genome. A total of 38 and 49 QTLs controlling yield and yield components were identified in F2: 3 and F2: 4 populations, respectively. Analyses of these QTLs indicated that the effects of partial dominance and overdominance contributed to heterosis in Upland cotton simultaneously. Most of the QTLs showed partial dominance whereas 13 QTLs showing overdominance in F2:3 population, and 19 QTLs showed overdominance in F2:4. Among them, 21 QTLs were common in both F2: 3 and F2: 4 populations. A large number of two-locus interactions for yield and yield components were detected in both generations. AA (additive × additive) epistasis accounted for majority portion of epistatic effects. Thirty three complementary two-locus homozygotes (11/22 and 22/11) were the best genotypes for AA interactions in terms of bolls per plant. Genotypes of double homozygotes, 11/22, 22/11 and 22/22, performed best for AD/DA interactions, while genotype of 11/12 performed best for DD interactions. These results indicated that (1) partial dominance and overdominance effects at single-locus level and (2) epistasis at two-locus level elucidated the genetic basis of heterosis in Upland cotton. PMID:26618635

Multifactor dimensionality reduction (MDR) was developed as a method for detecting statistical patterns of epistasis. The overall goal of MDR is to change the representation space of the data to make interactions easier to detect. It is well known that machine learning methods may not provide robust models when the class variable (e.g. case-control status) is imbalanced and accuracy is used as the fitness measure. This is because most methods learn patterns that are relevant for the larger of the two classes. The goal of this study was to evaluate three different strategies for improving the power of MDR to detect epistasis in imbalanced datasets. The methods evaluated were: (1) over-sampling that resamples with replacement the smaller class until the data are balanced, (2) under-sampling that randomly removes subjects from the larger class until the data are balanced, and (3) balanced accuracy [(sensitivity+specificity)/2] as the fitness function with and without an adjusted threshold. These three methods were compared using simulated data with two-locus epistatic interactions of varying heritability (0.01, 0.025, 0.05, 0.1, 0.2, 0.3, 0.4) and minor allele frequency (0.2, 0.4) that were embedded in 100 replicate datasets of varying sample sizes (400, 800, 1600). Each dataset was generated with different ratios of cases to controls (1 : 1, 1 : 2, 1 : 4). We found that the balanced accuracy function with an adjusted threshold significantly outperformed both over-sampling and under-sampling and fully recovered the power. These results suggest that balanced accuracy should be used instead of accuracy for the MDR analysis of epistasis in imbalanced datasets. (c) 2007 Wiley-Liss, Inc.

Full Text Available During the past decade, findings of genome-wide association studies (GWAS improved our knowledge and understanding of disease genetics. To date, thousands of SNPs have been associated to diseases and other complex traits. Statistical analysis typically looks for association between a phenotype and a SNP taken individually via single-locus tests. However, geneticists admit this is an oversimplified approach to tackle the complexity of underlying biological mechanisms. Interaction between SNPs, namely epistasis, must be considered. Unfortunately, epistasis detection gives rise to analytic challenges since analyzing every SNP combination is at present impractical at a genome-wide scale. In this review, we will present the main strategies recently proposed to detect epistatic interactions, along with their operating principle. Some of these methods are exhaustive, such as multifactor dimensionality reduction, likelihood ratio-based tests or receiver operating characteristic curve analysis; some are non-exhaustive, such as machine learning techniques (random forests, Bayesian networks or combinatorial optimization approaches (ant colony optimization, computational evolution system.

Here we introduce the multifactor dimensionality reduction (MDR) methodology and software package for detecting and characterizing epistasis in genetic association studies. We provide a general overview of the method and then highlight some of the key functions of the open-source MDR software package that is freely distributed. We end with a few examples of published studies of complex human diseases that have used MDR.

In this article we focus on how the hierarchical and single-path assumptions of epistasis analysis can bias the inference of gene regulatory networks. Here we emphasize the critical importance of dynamic analyses, and specifically illustrate the use of Boolean network models. Epistasis in a broad sense refers to gene interactions, however, as originally proposed by Bateson, epistasis is defined as the blocking of a particular allelic effect due to the effect of another allele at a different locus (herein, classical epistasis). Classical epistasis analysis has proven powerful and useful, allowing researchers to infer and assign directionality to gene interactions. As larger data sets are becoming available, the analysis of classical epistasis is being complemented with computer science tools and system biology approaches. We show that when the hierarchical and single-path assumptions are not met in classical epistasis analysis, the access to relevant information and the correct inference of gene interaction topologies is hindered, and it becomes necessary to consider the temporal dynamics of gene interactions. The use of dynamical networks can overcome these limitations. We particularly focus on the use of Boolean networks that, like classical epistasis analysis, relies on logical formalisms, and hence can complement classical epistasis analysis and relax its assumptions. We develop a couple of theoretical examples and analyze them from a dynamic Boolean network model perspective. Boolean networks could help to guide additional experiments and discern among alternative regulatory schemes that would be impossible or difficult to infer without the elimination of these assumption from the classical epistasis analysis. We also use examples from the literature to show how a Boolean network-based approach has resolved ambiguities and guided epistasis analysis. Our article complements previous accounts, not only by focusing on the implications of the hierarchical and

Genome-wide association studies (GWASs) and other high-throughput initiatives have led to an information explosion in human genetics and genetic epidemiology. Conversion of this wealth of new information about genomic variation to knowledge about public health and human biology will depend critically on the complexity of the genotype to phenotype mapping relationship. We review here computational approaches to genetic analysis that embrace, rather than ignore, the complexity of human health. We focus on multifactor dimensionality reduction (MDR) as an approach for modeling one of these complexities: epistasis or gene-gene interaction.

Full Text Available In this review we focus on how the hierarchical and single-path assumptions of epistasis analysis can bias the topologies of gene interactions infered. This has been acknowledged in several previous papers and reviews, but here we emphasize the critical importance of dynamic analyses, and specifically illustrate the use of Boolean network models. Epistasis in a broad sense refers to gene interactions, however, as originally proposed by Bateson (herein, classical epistasis, defined as the blocking of a particular allelic effect due to the effect of another allele at a different locus. Classical epistasis analysis has proven powerful and useful, allowing researchers to infer and assign directionality to gene interactions. As larger data sets are becoming available, the analysis of classical epistasis is being complemented with computer science tools and system biology approaches. We show that when the hierarchical and single-path assumptions are not met in classical epistasis analysis, the access to relevant information and the correct gene interaction topologies are hindered, and it becomes necessary to consider the temporal dynamics of gene interactions. The use of dynamical networks can overcome these limitations. We particularly focus on the use of Boolean networks that, like classical epistasis analysis, relies on logical formalisms, and hence can complement classical epistasis analysis and relax its assumptions. We develop a couple of theoretical examples and analyze them from a dynamic Boolean network model perspective. Boolean networks could help to guide additional experiments and discern among alternative regulatory schemes that would be impossible or difficult to infer without the elimination of these assumption from the classical epistasis analysis. We also use examples from the literature to show how a Boolean network-based approach has resolved ambiguities and guided epistasis analysis. Our review complements previous accounts, not

Environmental changes trigger cellular responses, but also impose selective pressures on the underlying regulatory systems. To disentangle this complex interplay we follow a synthetic biology approach. By linking the output of regulatory systems to bacterial growth, quantified temporally variable selective pressures can be applied to regulatory systems. This approach allows one to explore how networks evolve in complex variable environments. Epistatic interactions that underlie evolutionary constraint have mainly been studied for constant external conditions. However, environmental changes may modulate epistasis and hence affect genetic constraints. We investigate genetic constraints in the adaptive evolution of a novel regulatory function in variable environments, using the lac repressor, LacI, as a model system. We systematically reconstructed mutational trajectories from wild type LacI to three different variants that each exhibit an inverse response to the inducing ligand IPTG, and analyzed the higher-order interactions between genetic and environmental changes. We find epistasis to depend strongly on the environment. As a result, mutational steps essential to inversion but inaccessible by positive selection in one environment, become accessible in another. We present a graphical method to analyze the observed complex higher-order interactions between multiple mutations and environmental change, and show how they can be explained by a combination of mutational effects on allostery and thermodynamic stability. This dependency of genetic constraint on the environment should fundamentally affect evolutionary dynamics and phylogenetic analysis. NWO-FOM

QTL mapping based on backcross and RIL populations suggests that epistasis together with partial dominance, over-dominance and their environmental interactions of QTLs play an important role in yield heterosis in upland cotton. A backcross population (BC) was constructed to explore the genetic basis of heterosis in upland cotton (Gossypium hirsutum L.). For yield and yield components, recombinant inbred line (RIL) and BC populations were evaluated simultaneously at three different locations. A total of 35 and 30 quantitative trait loci (QTLs) were detected based on the RILs and BC data, respectively. Six (16.7 %) additive QTLs, 19 (52.8 %) partial dominant QTLs and 11 (30.6 %) over-dominant QTLs were detected by single-locus analysis using composite interval mapping in BC population. QTLs detected for mid-parent heterosis (MPH) were mostly related to those detected in the BC population. No significant correlation was found between marker heterozygosity and performance. It indicated that heterozygosity was not always favorable for performance. Two-locus analysis revealed 46, 25 and 12 QTLs with main effects (M-QTLs), and 55, 63 and 33 QTLs involved in digenic interactions (E-QTLs) were detected for yield and yield components in RIL, BC and MPH, respectively. A large number of M-QTLs and E-QTLs showed QTL by environment interactions (QEs) in three environments. These results suggest that epistasis together with partial dominance, over-dominance and QEs all contribute to yield heterosis in upland cotton.

Roots are involved in acquisition of water and nutrients, as well as in providing structural support to plant. The root system provides a dynamic model for developmental analysis. Here, we investigated quantitative trait loci (QTL), dynamic conditional QTL and epistatic interactions for seedling root traits using an upland cotton F2 population and a constructed genetic map. Totally, 37 QTLs for root traits, 35 dynamic conditional QTLs based on the net increased amount of root traits (root tips, forks, length, surface area and volume) (i) after transplanting 10 days compared to 5 days, and (ii) after transplanting 15 days to 10 days were detected. Obvious dynamic characteristic of QTL and dynamic conditional QTL existed at different developmental stages of root because QTL and dynamic conditional QTL had not been detected simultaneously. We further confirmed that additive and dominance effects of QTL qRSA-chr1-1 in interval time 5 to 10 DAT (days after transplant) offset the effects in 10 to 15 DAT. Lots of two-locus interactions for root traits were identified unconditionally or dynamically, and a few epistatic interactions were only detected simultaneously in interval time of 5-10 DAT and 10-15 DAT, suggesting different interactive genetic mechanisms on root development at different stages. Dynamic conditional QTL and epistasis effects provide new attempts to understand the dynamics of roots and provide clues for root architecture selection in upland cotton.

We investigated the genetic associations of ischemic stroke by identifying epistasis of its heterogeneous subtypes such as small vessel occlusion (SVO) and large artery atherosclerosis (LAA). Epistasis was analyzed with 24 genes in 207 controls and 271 patients (SVO = 110, LAA = 95) using multifactor dimensionality reduction and entropy decomposition. The multifactor dimensionality reduction analysis with any of 1- to 4-locus models showed no significant association with LAA (P > 0.05). The analysis of SVO, however, revealed a significant association in the best 3-locus model with P10L of TGF-beta1, C1013T of SPP1, and R485K of F5 (testing balanced accuracy = 63.17%, P < 0.05). Subsequent entropy analysis also revealed that such heterogeneity was present and quite a large entropy was estimated among the 3 loci for SVO (5.43%), but only a relatively small entropy was estimated for LAA (1.81%). This suggests that the synergistic epistasis model might contribute specifically to the pathogenetsis of SVO, which implies a different etiopathogenesis of the ischemic stroke subtypes. [BMB reports 2009; 42(9): 617-622].

Epistasis plays an essential rule in understanding the regulation mechanisms and is an essential component of the genetic architecture of the gene expressions. However, interaction analysis of gene expressions remains fundamentally unexplored due to great computational challenges and data availability. Due to variation in splicing, transcription start sites, polyadenylation sites, post-transcriptional RNA editing across the entire gene, and transcription rates of the cells, RNA-seq measurements generate large expression variability and collectively create the observed position level read count curves. A single number for measuring gene expression which is widely used for microarray measured gene expression analysis is highly unlikely to sufficiently account for large expression variation across the gene. Simultaneously analyzing epistatic architecture using the RNA-seq and whole genome sequencing (WGS) data poses enormous challenges. We develop a nonlinear functional regression model (FRGM) with functional responses where the position-level read counts within a gene are taken as a function of genomic position, and functional predictors where genotype profiles are viewed as a function of genomic position, for epistasis analysis with RNA-seq data. Instead of testing the interaction of all possible pair-wises SNPs, the FRGM takes a gene as a basic unit for epistasis analysis, which tests for the interaction of all possible pairs of genes and use all the information that can be accessed to collectively test interaction between all possible pairs of SNPs within two genome regions. By large-scale simulations, we demonstrate that the proposed FRGM for epistasis analysis can achieve the correct type 1 error and has higher power to detect the interactions between genes than the existing methods. The proposed methods are applied to the RNA-seq and WGS data from the 1000 Genome Project. The numbers of pairs of significantly interacting genes after Bonferroni correction

Unraveling the factors that determine the rate of adaptation is a major question in evolutionary biology. One key parameter is the effect of a new mutation on fitness, which invariably depends on the environment and genetic background. The fate of a mutation also depends on population size, which determines the amount of drift it will experience. Here, we manipulate both population size and genotype composition and follow adaptation of 23 distinct Escherichia coli genotypes. These have previously accumulated mutations under intense genetic drift and encompass a substantial fitness variation. A simple rule is uncovered: the net fitness change is negatively correlated with the fitness of the genotype in which new mutations appear—a signature of epistasis. We find that Fisher's geometrical model can account for the observed patterns of fitness change and infer the parameters of this model that best fit the data, using Approximate Bayesian Computation. We estimate a genomic mutation rate of 0.01 per generation for fitness altering mutations, albeit with a large confidence interval, a mean fitness effect of mutations of −0.01, and an effective number of traits nine in mutS− E. coli. This framework can be extended to confront a broader range of models with data and test different classes of fitness landscape models. PMID:24372601

Type 2 diabetes mellitus is a complex genetic disease, which results from interactions between multiple genes and environmental factors without any single factor having strong independent effects. This study was done to identify gene to gene interactions which could be associated with the risk of Type 2 diabetes. We genotyped 23 different loci in the 15 candidate genes of Type 2 diabetes in 504 unrelated Type 2 diabetic patients and 133 non-diabetic control subjects. We analysed gene to gene interactions among 23 polymorphic loci using the multifactor-dimensionality reduction (MDR) method, which has been shown to be effective for detecting and characterising gene to gene interactions in case-control studies with relatively small samples. The MDR analysis showed a significant gene to gene interaction between the Ala55Val polymorphism in the uncoupling protein 2 gene ( UCP2) and the 161C>T polymorphism in the exon 6 of peroxisome proliferator-activated receptor gamma ( PPARgamma) gene. This interaction showed the maximum consistency and minimum prediction error among all gene to gene interaction models evaluated. Moreover, the combination of the UCP2 55 Ala/Val heterozygote and the PPARgamma 161 C/C homozygote was associated with a reduced risk of Type 2 diabetes (odds ratio: 0.51, 95% CI: 0.34 to 0.77, p=0.0016). Using the MDR method, we showed a two-locus interaction between the UCP2 and PPARgamma genes among 23 loci in the candidate genes of Type 2 diabetes. The determination of such genotype combinations contributing to Type 2 diabetes mellitus could provide a new tool for identifying high-risk individuals.

Genetic interactions are keys to understand complex traits and evolution. Epistasis analysis is an effective method to map genetic interactions. Large-scale quantitative epistasis analysis has been well established for single cells. However, there is a substantial lack of such studies in multicellular organisms and their complex phenotypes such as development. Here we present a method to extend quantitative epistasis analysis to developmental traits. In the nematode Caenorhabditis elegans, we applied RNA interference on mutants to inactivate two genes, used an imaging system to quantitatively measure phenotypes, and developed a set of statistical methods to extract genetic interactions from phenotypic measurement. Using two different C. elegans developmental phenotypes, body length and sex ratio, as examples, we showed that this method could accommodate various metazoan phenotypes with performances comparable to those methods in single cell growth studies. Comparing with qualitative observations, this method of quantitative epistasis enabled detection of new interactions involving subtle phenotypes. For example, several sex-ratio genes were found to interact with brc-1 and brd-1, the orthologs of the human breast cancer genes BRCA1 and BARD1, respectively. We confirmed the brc-1 interactions with the following genes in DNA damage response: C34F6.1, him-3 (ortholog of HORMAD1, HORMAD2), sdc-1, and set-2 (ortholog of SETD1A, SETD1B, KMT2C, KMT2D), validating the effectiveness of our method in detecting genetic interactions. We developed a reliable, high-throughput method for quantitative epistasis analysis of developmental phenotypes.

Full Text Available Although gene-gene interaction, or epistasis, plays a large role in complex traits in model organisms, genome-wide by genome-wide searches for two-way interaction have limited power in human studies. We thus used knowledge of a biological pathway in order to identify a contribution of epistasis to autism spectrum disorders (ASDs in humans, a reverse-pathway genetic approach. Based on previous observation of increased ASD symptoms in Mendelian disorders of the Ras/MAPK pathway (RASopathies, we showed that common SNPs in RASopathy genes show enrichment for association signal in GWAS (P = 0.02. We then screened genome-wide for interactors with RASopathy gene SNPs and showed strong enrichment in ASD-affected individuals (P < 2.2 x 10-16, with a number of pairwise interactions meeting genome-wide criteria for significance. Finally, we utilized quantitative measures of ASD symptoms in RASopathy-affected individuals to perform modifier mapping via GWAS. One top region overlapped between these independent approaches, and we showed dysregulation of a gene in this region, GPR141, in a RASopathy neural cell line. We thus used orthogonal approaches to provide strong evidence for a contribution of epistasis to ASDs, confirm a role for the Ras/MAPK pathway in idiopathic ASDs, and to identify a convergent candidate gene that may interact with the Ras/MAPK pathway.

Full Text Available Abstract Background Human geneticists are now capable of measuring more than one million DNA sequence variations from across the human genome. The new challenge is to develop computationally feasible methods capable of analyzing these data for associations with common human disease, particularly in the context of epistasis. Epistasis describes the situation where multiple genes interact in a complex non-linear manner to determine an individual's disease risk and is thought to be ubiquitous for common diseases. Multifactor Dimensionality Reduction (MDR is an algorithm capable of detecting epistasis. An exhaustive analysis with MDR is often computationally expensive, particularly for high order interactions. This challenge has previously been met with parallel computation and expensive hardware. The option we examine here exploits commodity hardware designed for computer graphics. In modern computers Graphics Processing Units (GPUs have more memory bandwidth and computational capability than Central Processing Units (CPUs and are well suited to this problem. Advances in the video game industry have led to an economy of scale creating a situation where these powerful components are readily available at very low cost. Here we implement and evaluate the performance of the MDR algorithm on GPUs. Of primary interest are the time required for an epistasis analysis and the price to performance ratio of available solutions. Findings We found that using MDR on GPUs consistently increased performance per machine over both a feature rich Java software package and a C++ cluster implementation. The performance of a GPU workstation running a GPU implementation reduces computation time by a factor of 160 compared to an 8-core workstation running the Java implementation on CPUs. This GPU workstation performs similarly to 150 cores running an optimized C++ implementation on a Beowulf cluster. Furthermore this GPU system provides extremely cost effective

Human geneticists are now capable of measuring more than one million DNA sequence variations from across the human genome. The new challenge is to develop computationally feasible methods capable of analyzing these data for associations with common human disease, particularly in the context of epistasis. Epistasis describes the situation where multiple genes interact in a complex non-linear manner to determine an individual's disease risk and is thought to be ubiquitous for common diseases. Multifactor Dimensionality Reduction (MDR) is an algorithm capable of detecting epistasis. An exhaustive analysis with MDR is often computationally expensive, particularly for high order interactions. This challenge has previously been met with parallel computation and expensive hardware. The option we examine here exploits commodity hardware designed for computer graphics. In modern computers Graphics Processing Units (GPUs) have more memory bandwidth and computational capability than Central Processing Units (CPUs) and are well suited to this problem. Advances in the video game industry have led to an economy of scale creating a situation where these powerful components are readily available at very low cost. Here we implement and evaluate the performance of the MDR algorithm on GPUs. Of primary interest are the time required for an epistasis analysis and the price to performance ratio of available solutions. We found that using MDR on GPUs consistently increased performance per machine over both a feature rich Java software package and a C++ cluster implementation. The performance of a GPU workstation running a GPU implementation reduces computation time by a factor of 160 compared to an 8-core workstation running the Java implementation on CPUs. This GPU workstation performs similarly to 150 cores running an optimized C++ implementation on a Beowulf cluster. Furthermore this GPU system provides extremely cost effective performance while leaving the CPU available for other

Full Text Available Although consensus has now been reached on a general two-locus DNA barcode for land plants, the selected combination of markers (rbcL + matK is not applicable for ferns at the moment. Yet especially for ferns, DNA barcoding is potentially of great value since fern gametophytes--while playing an essential role in fern colonization and reproduction--generally lack the morphological complexity for morphology-based identification and have therefore been underappreciated in ecological studies. We evaluated the potential of a combination of rbcL with a noncoding plastid marker, trnL-F, to obtain DNA-identifications for fern species. A regional approach was adopted, by creating a reference database of trusted rbcL and trnL-F sequences for the wild-occurring homosporous ferns of NW-Europe. A combination of parsimony analyses and distance-based analyses was performed to evaluate the discriminatory power of the two-region barcode. DNA was successfully extracted from 86 tiny fern gametophytes and was used as a test case for the performance of DNA-based identification. Primer universality proved high for both markers. Based on the combined rbcL + trnL-F dataset, all genera as well as all species with non-equal chloroplast genomes formed their own well supported monophyletic clade, indicating a high discriminatory power. Interspecific distances were larger than intraspecific distances for all tested taxa. Identification tests on gametophytes showed a comparable result. All test samples could be identified to genus level, species identification was well possible unless they belonged to a pair of Dryopteris species with completely identical chloroplast genomes. Our results suggest a high potential of the combined use of rbcL and trnL-F as a two-locus cpDNA barcode for identification of fern species. A regional approach may be preferred for ecological tests. We here offer such a ready-to-use barcoding approach for ferns, which opens the way for answering a

Owed to their reduced size and low number of proteins encoded, RNA viruses and other subviral pathogens are often considered as being genetically too simple. However, this structural simplicity also creates the necessity for viral RNA sequences to encode for more than one protein and for proteins to carry out multiple functions, all together resulting in complex patterns of genetic interactions. In this work we will first review the experimental studies revealing that the architecture of viral genomes is dominated by antagonistic interactions among loci. Second, we will also review mathematical models and provide a description of computational tools for the study of RNA virus dynamics and evolution. As an application of these tools, we will finish this review article by analyzing a stochastic bit-string model of in silico virus replication. This model analyzes the interplay between epistasis and the mode of replication on determining the population load of deleterious mutations. The model suggests that, for a given mutation rate, the deleterious mutational load is always larger when epistasis is predominantly antagonistic than when synergism is the rule. However, the magnitude of this effect is larger if replication occurs geometrically than if it proceeds linearly.

Full Text Available Many birth defects and genetic diseases are expressed in individuals that do not carry the disease causing alleles. Genetic diseases observed in offspring can be caused by gene expression in mothers and by interactions between gene expression in mothers and offspring. It is not clear whether the underlying pattern of gene expression (maternal versus offspring affects the incidence of genetic disease. Here we develop a 2-locus population genetic model with epistatic interactions between a maternal gene and a zygotic gene to address this question. We show that maternal effect genes that affect disease susceptibility in offspring persist longer and at higher frequencies in a population than offspring genes with the same effects. We find that specific forms of maternal-zygotic epistasis can maintain disease causing alleles at high frequencies over a range of plausible values. Our findings suggest that the strength and form of epistasis and the underlying pattern of gene expression may greatly influence the prevalence of human genetic diseases.

Full Text Available The efectiveness of selection depends on the gene action cotrolling the character. The presence of epistatic gene action will delay the genetic gain in self pollinated crops like soybean. The objective of this research was to obtain information on genetic control of soybean tolerance to aluminum toxicity on nutrient culture. This research was conducted at green house of the University Farm IPB Cikabayan, Bogor, from April to June 2013. This research used 120 seedlings of F2 population generated from crossing between Argomulyo (Al-sensitive with Tanggamus (Al-tolerant. Seedlings were grown in nutrient culture for 14 days with Al concentration of 1.5 mM and pH 4.0, to observe the vegetative growth under aluminum stress condition. The result showed that mean of roots length, shoot length, shoot to root ratio, wet and dry weight of root and shoot exceeded both parents mean value with moderate to high heritability. All observed characters had continue distribution pattern, and controlled by many genes. Duplicate epistasis additive gene action controlled only root length while other characters were controlled by complementary epistasis gene action.Keywords: gene action, heritability, nutrient culture, selection, tocixity

Full Text Available We propose a novel multifactor dimensionality reduction method for epistasis detection in small or extended pedigrees, FAM-MDR. It combines features of the Genome-wide Rapid Association using Mixed Model And Regression approach (GRAMMAR with Model-Based MDR (MB-MDR. We focus on continuous traits, although the method is general and can be used for outcomes of any type, including binary and censored traits. When comparing FAM-MDR with Pedigree-based Generalized MDR (PGMDR, which is a generalization of Multifactor Dimensionality Reduction (MDR to continuous traits and related individuals, FAM-MDR was found to outperform PGMDR in terms of power, in most of the considered simulated scenarios. Additional simulations revealed that PGMDR does not appropriately deal with multiple testing and consequently gives rise to overly optimistic results. FAM-MDR adequately deals with multiple testing in epistasis screens and is in contrast rather conservative, by construction. Furthermore, simulations show that correcting for lower order (main effects is of utmost importance when claiming epistasis. As Type 2 Diabetes Mellitus (T2DM is a complex phenotype likely influenced by gene-gene interactions, we applied FAM-MDR to examine data on glucose area-under-the-curve (GAUC, an endophenotype of T2DM for which multiple independent genetic associations have been observed, in the Amish Family Diabetes Study (AFDS. This application reveals that FAM-MDR makes more efficient use of the available data than PGMDR and can deal with multi-generational pedigrees more easily. In conclusion, we have validated FAM-MDR and compared it to PGMDR, the current state-of-the-art MDR method for family data, using both simulations and a practical dataset. FAM-MDR is found to outperform PGMDR in that it handles the multiple testing issue more correctly, has increased power, and efficiently uses all available information.

We propose a novel multifactor dimensionality reduction method for epistasis detection in small or extended pedigrees, FAM-MDR. It combines features of the Genome-wide Rapid Association using Mixed Model And Regression approach (GRAMMAR) with Model-Based MDR (MB-MDR). We focus on continuous traits, although the method is general and can be used for outcomes of any type, including binary and censored traits. When comparing FAM-MDR with Pedigree-based Generalized MDR (PGMDR), which is a generalization of Multifactor Dimensionality Reduction (MDR) to continuous traits and related individuals, FAM-MDR was found to outperform PGMDR in terms of power, in most of the considered simulated scenarios. Additional simulations revealed that PGMDR does not appropriately deal with multiple testing and consequently gives rise to overly optimistic results. FAM-MDR adequately deals with multiple testing in epistasis screens and is in contrast rather conservative, by construction. Furthermore, simulations show that correcting for lower order (main) effects is of utmost importance when claiming epistasis. As Type 2 Diabetes Mellitus (T2DM) is a complex phenotype likely influenced by gene-gene interactions, we applied FAM-MDR to examine data on glucose area-under-the-curve (GAUC), an endophenotype of T2DM for which multiple independent genetic associations have been observed, in the Amish Family Diabetes Study (AFDS). This application reveals that FAM-MDR makes more efficient use of the available data than PGMDR and can deal with multi-generational pedigrees more easily. In conclusion, we have validated FAM-MDR and compared it to PGMDR, the current state-of-the-art MDR method for family data, using both simulations and a practical dataset. FAM-MDR is found to outperform PGMDR in that it handles the multiple testing issue more correctly, has increased power, and efficiently uses all available information.

Full Text Available The existence of epistasis in humans was first predicted by Bateson in 1909. Epistasis describes the non-linear, synergistic interaction of two or more genetic loci, which can substantially modify disease severity or result in entirely new phenotypes. The concept has remained controversial in human genetics because of the lack of well-characterized examples. In humans, it is only possible to demonstrate epistasis if two or more genes are mutated. In most cases of epistasis, the mutated gene products are likely to be constituents of the same physiological pathway leading to severe disruption of a cellular function such as antibody production. We have recently described a digenic family, who carry mutations of TNFRSF13B/TACI as well as TCF3 genes. Both genes lie in tandem along the immunoglobulin isotype switching and secretion pathway. We have shown they interact in an epistatic way causing severe immunodeficiency and autoimmunity in the digenic proband. With the advent of next generation sequencing, it is likely other families with digenic inheritance will be identified. Since digenic inheritance does not always cause epistasis, we propose an epistasis index which may help quantify the effects of the two mutations. We also discuss the clinical implications of digenic inheritance and epistasis in humans with primary immunodeficiency disorders.

The effect of a mutation on the organism often depends on what other mutations are already present in its genome. Geneticists refer to such mutational interactions as epistasis. Pairwise epistatic effects have been recognized for over a century, and their evolutionary implications have received theoretical attention for nearly as long. However, pairwise epistatic interactions themselves can vary with genomic background. This is called higher-order epistasis, and its consequences for evolution are much less well understood. Here, we assess the influence that higher-order epistasis has on the topography of 16 published, biological fitness landscapes. We find that on average, their effects on fitness landscape declines with order, and suggest that notable exceptions to this trend may deserve experimental scrutiny. We conclude by highlighting opportunities for further theoretical and experimental work dissecting the influence that epistasis of all orders has on fitness landscape topography and on the efficiency of evolution by natural selection.

Although consensus has now been reached on a general two-locus DNA barcode for land plants, the selected combination of markers (rbcL + matK) is not applicable for ferns at the moment. Yet especially for ferns, DNA barcoding is potentially of great value since fern gametophytes—while playing an

Full Text Available Identifying and quantifying the benefits of sex and recombination is a long-standing problem in evolutionary theory. In particular, contradictory claims have been made about the existence of a benefit of recombination on high dimensional fitness landscapes in the presence of sign epistasis. Here we present a comparative numerical study of sexual and asexual evolutionary dynamics of haploids on tunably rugged model landscapes under strong selection, paying special attention to the temporal development of the evolutionary advantage of recombination and the link between population diversity and the rate of adaptation. We show that the adaptive advantage of recombination on static rugged landscapes is strictly transitory. At early times, an advantage of recombination arises through the possibility to combine individually occurring beneficial mutations, but this effect is reversed at longer times by the much more efficient trapping of recombining populations at local fitness peaks. These findings are explained by means of well-established results for a setup with only two loci. In accordance with the Red Queen hypothesis the transitory advantage can be prolonged indefinitely in fluctuating environments, and it is maximal when the environment fluctuates on the same time scale on which trapping at local optima typically occurs.

Mitochondria are involved in ageing and their function requires coordinated action of both mitochondrial and nuclear genes. Epistasis between the two genomes can influence lifespan but whether this also holds for reproductive senescence is unclear. Maternal inheritance of mitochondria predicts se...

Understanding epistasis is central to biology. For instance, epistatic interactions determine the topography of the fitness landscape and affect the dynamics and determinism of adaptation. However, few empirical data are available and comparing results is complicated by confounding variation in the

Full Text Available Despite the enormous investments made in collecting DNA samples and generating germline variation data across thousands of individuals in modern genome wide association studies (GWAS, progress has been frustratingly slow in explaining much of the heritability in common disease. Today’s paradigm of testing independent hypotheses on each SNP marker is unlikely to adequately reflect the complex biological processes in disease risk. Alternatively, modeling risk as an ensemble of SNPs that act in concert in a pathway, and/or interact non-additively on log risk for example, may be a more sensible way to approach gene mapping in modern studies. Implementing such analyses genome-wide can quickly become intractable due to the fact that even modest size SNP panels on modern genotype arrays (500k markers pose a combinatorial nightmare, require tens of billions of models to be tested for evidence of interaction. In this article, we provide an in-depth analysis of programs that have been developed to explicitly overcome these enormous computational barriers through the use of processors on graphics cards known as Graphics Processing Units (GPU. We include tutorials on GPU technology, which will convey why they are growing in appeal with today’s numerical scientists. One obvious advantage is the impressive density of microprocessor cores that are available on only a single GPU. Whereas high end servers feature up to 24 Intel or AMD CPU cores, the latest GPU offerings from nVidia feature over 2,600 cores. Each compute node may be outfitted with up to 4 GPU devices. Success on GPUs varies across problems. However epistasis screens fare well due to the high degree of parallelism exposed in these problems. Papers that we review routinely report GPU speedups of over two orders of magnitude (>100x over standard CPU implementations.

Full Text Available Genomic selection (GS procedures have proven useful in estimating breeding value and predicting phenotype with genome-wide molecular marker information. However, issues of high dimensionality, multicollinearity, and the inability to deal effectively with epistasis can jeopardize accuracy and predictive ability. We, therefore, propose a new nonparametric method, pRKHS, which combines the features of supervised principal component analysis (SPCA and reproducing kernel Hilbert spaces (RKHS regression, with versions for traits with no/low epistasis, pRKHS-NE, to high epistasis, pRKHS-E. Instead of assigning a specific relationship to represent the underlying epistasis, the method maps genotype to phenotype in a nonparametric way, thus requiring fewer genetic assumptions. SPCA decreases the number of markers needed for prediction by filtering out low-signal markers with the optimal marker set determined by cross-validation. Principal components are computed from reduced marker matrix (called supervised principal components, SPC and included in the smoothing spline ANOVA model as independent variables to fit the data. The new method was evaluated in comparison with current popular methods for practicing GS, specifically RR-BLUP, BayesA, BayesB, as well as a newer method by Crossa et al., RKHS-M, using both simulated and real data. Results demonstrate that pRKHS generally delivers greater predictive ability, particularly when epistasis impacts trait expression. Beyond prediction, the new method also facilitates inferences about the extent to which epistasis influences trait expression.

Genomic selection (GS) procedures have proven useful in estimating breeding value and predicting phenotype with genome-wide molecular marker information. However, issues of high dimensionality, multicollinearity, and the inability to deal effectively with epistasis can jeopardize accuracy and predictive ability. We, therefore, propose a new nonparametric method, pRKHS, which combines the features of supervised principal component analysis (SPCA) and reproducing kernel Hilbert spaces (RKHS) regression, with versions for traits with no/low epistasis, pRKHS-NE, to high epistasis, pRKHS-E. Instead of assigning a specific relationship to represent the underlying epistasis, the method maps genotype to phenotype in a nonparametric way, thus requiring fewer genetic assumptions. SPCA decreases the number of markers needed for prediction by filtering out low-signal markers with the optimal marker set determined by cross-validation. Principal components are computed from reduced marker matrix (called supervised principal components, SPC) and included in the smoothing spline ANOVA model as independent variables to fit the data. The new method was evaluated in comparison with current popular methods for practicing GS, specifically RR-BLUP, BayesA, BayesB, as well as a newer method by Crossa et al., RKHS-M, using both simulated and real data. Results demonstrate that pRKHS generally delivers greater predictive ability, particularly when epistasis impacts trait expression. Beyond prediction, the new method also facilitates inferences about the extent to which epistasis influences trait expression.

Full Text Available Gene expression data has been used in lieu of phenotype in both classical and quantitative genetic settings. These two disciplines have separate approaches to measuring and interpreting epistasis, which is the interaction between alleles at different loci. We propose a framework for estimating and interpreting epistasis from a classical experiment that combines the strengths of each approach. A regression analysis step accommodates the quantitative nature of expression measurements by estimating the effect of gene deletions plus any interaction. Effects are selected by significance such that a reduced model describes each expression trait. We show how the resulting models correspond to specific hierarchical relationships between two regulator genes and a target gene. These relationships are the basic units of genetic pathways and genomic system diagrams. Our approach can be extended to analyze data from a variety of experiments, multiple loci, and multiple environments.

Recent archaeological studies of crop domestication have suggested a relatively slow spread and fixation of some key domestication traits, such as the loss of seed shattering. In contrast, genetic studies often indicate that domestication traits have a fairly simple genetic basis, which should facilitate their rapid evolution under selection. Here we examine previously underexplored factors that could account for this apparent disconnect: the roles of gene-by-gene interactions (epistasis) and...

Full Text Available The surface proteins of human influenza A viruses experience positive selection to escape both human immunity and, more recently, antiviral drug treatments. In bacteria and viruses, immune-escape and drug-resistant phenotypes often appear through a combination of several mutations that have epistatic effects on pathogen fitness. However, the extent and structure of epistasis in influenza viral proteins have not been systematically investigated. Here, we develop a novel statistical method to detect positive epistasis between pairs of sites in a protein, based on the observed temporal patterns of sequence evolution. The method rests on the simple idea that a substitution at one site should rapidly follow a substitution at another site if the sites are positively epistatic. We apply this method to the surface proteins hemagglutinin and neuraminidase of influenza A virus subtypes H3N2 and H1N1. Compared to a non-epistatic null distribution, we detect substantial amounts of epistasis and determine the identities of putatively epistatic pairs of sites. In particular, using sequence data alone, our method identifies epistatic interactions between specific sites in neuraminidase that have recently been demonstrated, in vitro, to confer resistance to the drug oseltamivir; these epistatic interactions are responsible for widespread drug resistance among H1N1 viruses circulating today. This experimental validation demonstrates the predictive power of our method to identify epistatic sites of importance for viral adaptation and public health. We conclude that epistasis plays a large role in shaping the molecular evolution of influenza viruses. In particular, sites with , which would normally not be identified as positively selected, can facilitate viral adaptation through epistatic interactions with their partner sites. The knowledge of specific interactions among sites in influenza proteins may help us to predict the course of antigenic evolution and

The tendency for genetic architectures to exhibit epistasis among mutations plays a central role in the modern synthesis of evolutionary biology and in theoretical descriptions of many evolutionary processes. Nevertheless, few studies unquestionably show whether, and how, mutations typically interact. Beneficial mutations are especially difficult to identify because of their scarcity. Consequently, epistasis among pairs of this important class of mutations has, to our knowledge, never before been explored. Interactions among genome components should be of special relevance in compacted genomes such as those of RNA viruses. To tackle these issues, we first generated 47 genotypes of vesicular stomatitis virus carrying pairs of nucleotide substitution mutations whose separated and combined deleterious effects on fitness were determined. Several pairs exhibited significant interactions for fitness, including antagonistic and synergistic epistasis. Synthetic lethals represented 50% of the latter. In a second set of experiments, 15 genotypes carrying pairs of beneficial mutations were also created. In this case, all significant interactions were antagonistic. Our results show that the architecture of the fitness depends on complex interactions among genome components. PMID:15492220

Full Text Available Undergraduate students in genetics and developmental biology courses often struggle with the concept of epistasis because they are unaware that the logic of gene interactions differs between enzymatic pathways and signaling pathways. If students try to develop and memorize a single simple rule for predicting epistatic relationships without taking into account the nature of the pathway under consideration, they can become confused by cases where the rule does not apply. To remedy this problem, we developed a short pre-/posttest, an in-class activity for small groups, and a series of clicker questions about recessive epistasis in the context of a signaling pathway that intersects with an enzymatic pathway. We also developed a series of homework problems that provide deliberate practice in applying concepts in epistasis to different pathways and experimental situations. Students show significant improvement from pretest to posttest, and perform well on homework and exam questions following this activity. Here we describe these materials, as well as the formative and summative assessment results from one group of students to show how the activities impact student learning.

High-throughput genotyping technologies (such as SNP-arrays) allow the rapid collection of up to a few million genetic markers of an individual. Detecting epistasis (based on 2-SNP interactions) in Genome-Wide Association Studies is an important but time consuming operation since statistical computations have to be performed for each pair of measured markers. Computational methods to detect epistasis therefore suffer from prohibitively long runtimes; e.g., processing a moderately-sized dataset consisting of about 500,000 SNPs and 5,000 samples requires several days using state-of-the-art tools on a standard 3 GHz CPU. In this paper, we demonstrate how this task can be accelerated using a combination of fine-grained and coarse-grained parallelism on two different computing systems. The first architecture is based on reconfigurable hardware (FPGAs) while the second architecture uses multiple GPUs connected to the same host. We show that both systems can achieve speedups of around four orders-of-magnitude compared to the sequential implementation. This significantly reduces the runtimes for detecting epistasis to only a few minutes for moderately-sized datasets and to a few hours for large-scale datasets.

Full Text Available The fitness landscape captures the relationship between genotype and evolutionary fitness and is a pervasive metaphor used to describe the possible evolutionary trajectories of adaptation. However, little is known about the actual shape of fitness landscapes, including whether valleys of low fitness create local fitness optima, acting as barriers to adaptive change. Here we provide evidence of a rugged molecular fitness landscape arising during an evolution experiment in an asexual population of Saccharomyces cerevisiae. We identify the mutations that arose during the evolution using whole-genome sequencing and use competitive fitness assays to describe the mutations individually responsible for adaptation. In addition, we find that a fitness valley between two adaptive mutations in the genes MTH1 and HXT6/HXT7 is caused by reciprocal sign epistasis, where the fitness cost of the double mutant prohibits the two mutations from being selected in the same genetic background. The constraint enforced by reciprocal sign epistasis causes the mutations to remain mutually exclusive during the experiment, even though adaptive mutations in these two genes occur several times in independent lineages during the experiment. Our results show that epistasis plays a key role during adaptation and that inter-genic interactions can act as barriers between adaptive solutions. These results also provide a new interpretation on the classic Dobzhansky-Muller model of reproductive isolation and display some surprising parallels with mutations in genes often associated with tumors.

Full Text Available Background The rate at which fitness declines as an organism's genome accumulates random mutations is an important variable in several evolutionary theories. At an intuitive level, it might seem natural that random mutations should tend to interact synergistically, such that the rate of mean fitness decline accelerates as the number of random mutations is increased. However, in a number of recent studies, a prevalence of antagonistic epistasis (the tendency of multiple mutations to have a mitigating rather than reinforcing effect has been observed. Results We studied in silico the net amount and form of epistatic interactions in RNA secondary structure folding by measuring the fraction of neutral mutants as a function of mutational distance d. We found a clear prevalence of antagonistic epistasis in RNA secondary structure folding. By relating the fraction of neutral mutants at distance d to the average neutrality at distance d, we showed that this prevalence derives from the existence of many compensatory mutations at larger mutational distances. Conclusions Our findings imply that the average direction of epistasis in simple fitness landscapes is directly related to the density with which fitness peaks are distributed in these landscapes.

Full Text Available Using newly developed methods and software, association mapping was conducted for chromium content and total sugar in tobacco leaf, based on four -omics datasets. Our objective was to collect data on genotype and phenotype for 60 leaf samples at four developmental stages, from three plant architectural positions and for three cultivars that were grown in two locations. Association mapping was conducted to detect genetic variants at quantitative trait SNP (QTS loci, quantitative trait transcript (QTT differences, quantitative trait protein (QTP variability, and quantitative trait metabolite (QTM changes, which can be summarized as QTX locus variation. The total heritabilities of the four -omics loci for both traits tested were 23.60% for epistasis and 15.26% for treatment interaction. Epistasis and environment × treatment interaction had important impacts on complex traits at all -omics levels. For decreasing chromium content and increasing total sugar in tobacco leaf, six methylated loci can be directly used for marker-assisted selection, and expression of ten QTTs, seven QTPs and six QTMs can be modified by selection or cultivation.

Full Text Available Haemoglobin variants, Sickle (HbS and foetal (HbF have been associated with malaria protection. This study explores epistatic interactions between HbS and HbF on malaria infection.The study was conducted between March 2004 and December 2013 within the sickle cell disease (SCD programme at Muhimbili National Hospital, Tanzania. SCD status was categorized into HbAA, HbAS and HbSS using hemoglobin electrophoresis and High Performance Liquid Chromatography (HPLC. HbF levels were determined by HPLC. Malaria was diagnosed using rapid diagnostic test and/or blood film. Logistic regression and generalized estimating equations models were used to evaluate associations between SCD status, HbF and malaria.2,049 individuals with age range 0-70 years, HbAA 311(15.2%, HbAS 241(11.8% and HbSS 1,497(73.1% were analysed. At enrolment, malaria prevalence was significantly higher in HbAA 13.2% compared to HbAS 1.24% and HbSS 1.34% (p<0.001. Mean HbF was lower in those with malaria compared to those without malaria in HbAA (0.43% vs 0.82% but was the reverse in HbSS (8.10% vs 5.59%. An increase in HbF was associated with a decrease in risk of malaria OR=0.50 (95%CI: 0.28, 0.90; p=0.021 in HbAA, whereas for HbSS the risk of malaria increased OR=2.94 (1.44, 5.98; p=0.003. A similar pattern was seen during multiple visits; HbAA OR=0.52 (0.34, 0.80; p=0.003 vs HbSS OR=2.01 (1.27, 3.23; p=0.003.Higher prevalence of malaria in HbAA compared to HbAS and HbSS confirmed the protective effect of HbS. Lower prevalence of malaria in HbAA with high HbF supports a protective effect of HbF. However, in HbSS, the higher prevalence of malaria with high levels of HbF suggests loss of malaria protection. This is the first epidemiological study to suggest a negative epistasis between HbF and HbS on malaria.

Full Text Available The Bateson-Dobzhansky-Muller model posits that hybrid incompatibilities result from genetic changes that accumulate during population divergence. Indeed, much effort in recent years has been devoted to identifying genes associated with hybrid incompatibilities, often with limited success, suggesting that hybrid sterility and inviability are frequently caused by complex interactions between multiple loci and not by single or a small number of gene pairs. Our previous study showed that the nature of epistasis between sterility-conferring QTL in the Drosophila persimilis-D. pseudoobscura bogotana species pair is highly specific. Here, we further dissect one of the three QTL underlying hybrid male sterility between these species and provide evidence for multiple factors within this QTL. This result indicates that the number of loci thought to contribute to hybrid dysfunction may have been underestimated, and we discuss how linkage and complex epistasis may be characteristic of the genetics of hybrid incompatibilities. We further pinpoint the location of one locus that confers hybrid male sterility when homozygous, dubbed "mule-like", to roughly 250 kilobases.

Full Text Available A major goal of human genetics is to elucidate the genetic architecture of human disease, with the goal of fueling improvements in diagnosis and the understanding of disease pathogenesis. The degree to which epistasis, or non-additive effects of risk alleles at different loci, accounts for common disease traits is hotly debated, in part because the conditions under which epistasis evolves are not well understood. Using both theory and evolutionary simulation, we show that the occurrence of common diseases (i.e. unfit phenotypes with frequencies on the order of 1% can, under the right circumstances, be expected to be driven primarily by synergistic epistatic interactions. Conditions that are necessary, collectively, for this outcome include a strongly non-linear phenotypic landscape, strong (but not too strong selection against the disease phenotype, and "noise" in the genotype-phenotype map that is both environmental (extrinsic, time-correlated and developmental (intrinsic, uncorrelated and, in both cases, neither too little nor too great. These results suggest ways in which geneticists might identify, a priori, those disease traits for which an "epistatic explanation" should be sought, and in the process better focus ongoing searches for risk alleles.

Divergent selection by pollinators can bring about strong reproductive isolation via changes at few genes of large effect. This has recently been demonstrated in sexually deceptive orchids, where studies (1) quantified the strength of reproductive isolation in the field; (2) identified genes that appear to be causal for reproductive isolation; and (3) demonstrated selection by analysis of natural variation in gene sequence and expression. In a group of closely related Ophrys orchids, specific floral scent components, namely n-alkenes, are the key floral traits that control specific pollinator attraction by chemical mimicry of insect sex pheromones. The genetic basis of species-specific differences in alkene production mainly lies in two biosynthetic genes encoding stearoyl-acyl carrier protein desaturases (SAD) that are associated with floral scent variation and reproductive isolation between closely related species, and evolve under pollinator-mediated selection. However, the implications of this genetic architecture of key floral traits on the evolutionary processes of pollinator adaptation and speciation in this plant group remain unclear. Here, we expand on these recent findings to model scenarios of adaptive evolutionary change at SAD2 and SAD5, their effects on plant fitness (i.e., offspring number), and the dynamics of speciation. Our model suggests that the two-locus architecture of reproductive isolation allows for rapid sympatric speciation by pollinator shift; however, the likelihood of such pollinator-mediated speciation is asymmetric between the two orchid species O. sphegodes and O. exaltata due to different fitness effects of their predominant SAD2 and SAD5 alleles. Our study not only provides insight into pollinator adaptation and speciation mechanisms of sexually deceptive orchids but also demonstrates the power of applying a modeling approach to the study of pollinator-driven ecological speciation.

Epistasis is a key factor in evolution since it determines which combinations of mutations provide adaptive solutions and which mutational pathways toward these solutions are accessible by natural selection. There is growing evidence for the pervasiveness of sign epistasis—a complete reversion of

OncoSimulR implements forward-time genetic simulations of biallelic loci in asexual populations with special focus on cancer progression. Fitness can be defined as an arbitrary function of genetic interactions between multiple genes or modules of genes, including epistasis, restrictions in the order of accumulation of mutations, and order effects. Mutation rates can differ among genes, and can be affected by (anti)mutator genes. Also available are sampling from simulations (including single-cell sampling), plotting the genealogical relationships of clones and generating and plotting fitness landscapes. Implemented in R and C ++, freely available from BioConductor for Linux, Mac and Windows under the GNU GPL license. Version 2.5.9 or higher available from: http://www.bioconductor.org/packages/devel/bioc/html/OncoSimulR.html . GitHub repository at: https://github.com/rdiaz02/OncoSimul. ramon.diaz@iib.uam.es. Supplementary data are available at Bioinformatics online.

Kawasaki disease (KD) is a pediatric acute multisystemic vasculitis complicated by development of coronary artery lesions. The breakthrough theory on KD etiopathogenesis points to pathogens/environmental factors triggered by northeastern wind coming from China. Natural Killer cells and T lymphocytes express the inhibitory/activating Killer Immunoglobulin-like Receptors (KIR) to elicit an immune response against pathogens by binding to human leukocyte antigens (HLA) class I epitopes. We first report on the role of KIR/HLA genetic epistasis in a sample of 100 Italian KD children. We genotyped KIR, HLA-A, HLA-B and HLA-C polymorphisms, and compared KD data with those from 270 Italian healthy donors. The HLA-A*11 ligand for KIR2DS2/2DS4/3DL2 was a KD susceptibility marker by itself (odds ratio (OR)=3.85, confidence interval (CI)=1.55-9.53, P=0.004). Although no epistasis between HLA-A*11 and KIR2DS2/S4 emerged, HLA-A*11 also engages KIR3DL2, a framework gene encoding for a pathogen sensor of CpG-oligodeoxynucleotides (CpG-ODN), and KD blood mononuclear cells are actually prone to pathogen CpG-ODN activation in the acute phase. Moreover, carriers of KIR2DS2/HLA-C1 and KIR2DL2/HLA-C1 were more frequent among KD, in keeping with data demonstrating the involvement of these HLA/KIR couples in autoimmune endothelial damage. The highest KD risk factor was observed among carriers of KIR2DL2 and two or more HLA ligands (OR=10.24, CI=1.87-56.28; P=0.007).

Here, we describe the results from the first variance heterogeneity Genome Wide Association Study (VGWAS) on yeast expression data. Using this forward genetics approach, we show that the genetic regulation of gene-expression in the budding yeast, Saccharomyces cerevisiae, includes mechanisms that can lead to variance heterogeneity in the expression between genotypes. Additionally, we performed a mean effect association study (GWAS). Comparing the mean and variance heterogeneity analyses, we find that the mean expression level is under genetic regulation from a larger absolute number of loci but that a higher proportion of the variance controlling loci were trans-regulated. Both mean and variance regulating loci cluster in regulatory hotspots that affect a large number of phenotypes; a single variance-controlling locus, mapping close to DIA2, was found to be involved in more than 10% of the significant associations. It has been suggested in the literature that variance-heterogeneity between the genotypes might be due to genetic interactions. We therefore screened the multi-locus genotype-phenotype maps for several traits where multiple associations were found, for indications of epistasis. Several examples of two and three locus genetic interactions were found to involve variance-controlling loci, with reports from the literature corroborating the functional connections between the loci. By using a new analytical approach to re-analyze a powerful existing dataset, we are thus able to both provide novel insights to the genetic mechanisms involved in the regulation of gene-expression in budding yeast and experimentally validate epistasis as an important mechanism underlying genetic variance-heterogeneity between genotypes.

Full Text Available Gastritis is a common but a serious disease with a potential risk of developing carcinoma. Helicobacter pylori infection is reported as the most common cause of gastritis, but other genetic and genomic factors exist, especially single-nucleotide polymorphisms (SNPs. Association studies between SNPs and gastritis disease are important, but results on epistatic interactions from multiple SNPs are rarely found in previous genome-wide association (GWA studies. In this study, we performed computational GWA case-control studies for gastritis in Korea Associated Resource (KARE data. By transforming the resulting SNP epistasis network into a gene-gene epistasis network, we also identified potential gene-gene interaction factors that affect the susceptibility to gastritis.

How do adapting populations navigate the tensions between the costs of gene expression and the benefits of gene products to optimize the levels of many genes at once? Here we combined independently-arising beneficial mutations that altered enzyme levels in the central metabolism of Methylobacterium extorquens to uncover the fitness landscape defined by gene expression levels. We found strong antagonism and sign epistasis between these beneficial mutations. Mutations with the largest individual benefit interacted the most antagonistically with other mutations, a trend we also uncovered through analyses of datasets from other model systems. However, these beneficial mutations interacted multiplicatively (i.e., no epistasis) at the level of enzyme expression. By generating a model that predicts fitness from enzyme levels we could explain the observed sign epistasis as a result of overshooting the optimum defined by a balance between enzyme catalysis benefits and fitness costs. Knowledge of the phenotypic landscape also illuminated that, although the fitness peak was phenotypically far from the ancestral state, it was not genetically distant. Single beneficial mutations jumped straight toward the global optimum rather than being constrained to change the expression phenotypes in the correlated fashion expected by the genetic architecture. Given that adaptation in nature often results from optimizing gene expression, these conclusions can be widely applicable to other organisms and selective conditions. Poor interactions between individually beneficial alleles affecting gene expression may thus compromise the benefit of sex during adaptation and promote genetic differentiation.

Antibiotic resistance often evolves by mutations at conserved sites in essential genes, resulting in parallel molecular evolution between divergent bacterial strains and species. Whether these resistance mutations are having parallel effects on fitness across bacterial taxa, however, is unclear. This is an important point to address, because the fitness effects of resistance mutations play a key role in the spread and maintenance of resistance in pathogen populations. We address this idea by measuring the fitness effect of a collection of rifampicin resistance mutations in the β subunit of RNA polymerase (rpoB) across eight strains that span the diversity of the genus Pseudomonas. We find that almost 50% of rpoB mutations have background-dependent fitness costs, demonstrating that epistatic interactions between rpoB and the rest of the genome are common. Moreover, epistasis is typically strong, and it is the dominant genetic determinant of the cost of resistance mutations. To investigate the functional basis of epistasis, and because rpoB plays a central role in transcription, we measured the effects of common rpoB mutations on transcriptional efficiency across three strains of Pseudomonas. Transcriptional efficiency correlates strongly to fitness across strains, and epistasis arises because individual rpoB mutations have differential effects on transcriptional efficiency in different genetic backgrounds. PMID:27170722

Full Text Available Studies of the evolution of development characterize the way in which gene regulatory dynamics during ontogeny constructs and channels phenotypic variation. These studies have identified a number of evolutionary regularities: (1 phenotypes occupy only a small subspace of possible phenotypes, (2 the influence of mutation is not uniform and is often canalized, and (3 a great deal of morphological variation evolved early in the history of multicellular life. An important implication of these studies is that diversity is largely the outcome of the evolution of gene regulation rather than the emergence of new, structural genes. Using a simple model that considers a generic property of developmental maps-the interaction between multiple genetic elements and the nonlinearity of gene interaction in shaping phenotypic traits-we are able to recover many of these empirical regularities. We show that visible phenotypes represent only a small fraction of possibilities. Epistasis ensures that phenotypes are highly clustered in morphospace and that the most frequent phenotypes are the most similar. We perform phylogenetic analyses on an evolving, developmental model and find that species become more alike through time, whereas higher-level grades have a tendency to diverge. Ancestral phenotypes, produced by early developmental programs with a low level of gene interaction, are found to span a significantly greater volume of the total phenotypic space than derived taxa. We suggest that early and late evolution have a different character that we classify into micro- and macroevolutionary configurations. These findings complement the view of development as a key component in the production of endless forms and highlight the crucial role of development in constraining biotic diversity and evolutionary trajectories.

Epistasis or gene-gene interaction is a fundamental component of the genetic architecture of complex traits such as disease susceptibility. Multifactor dimensionality reduction (MDR) was developed as a nonparametric and model-free method to detect epistasis when there are no significant marginal genetic effects. However, in many studies of complex disease, other covariates like age of onset and smoking status could have a strong main effect and may potentially interfere with MDR's ability to achieve its goal. In this paper, we present a simple and computationally efficient sampling method to adjust for covariate effects in MDR. We use simulation to show that after adjustment, MDR has sufficient power to detect true gene-gene interactions. We also compare our method with the state-of-art technique in covariate adjustment. The results suggest that our proposed method performs similarly, but is more computationally efficient. We then apply this new method to an analysis of a population-based bladder cancer study in New Hampshire. PMID:20924193

BACKGROUND: Epistasis is recognized as a fundamental part of the genetic architecture of individuals. Several computational approaches have been developed to model gene-gene interactions in case-control studies, however, none of them is suitable for time-dependent analysis. Herein we introduce the

textabstractDespite recent discoveries in the genetics of sporadic Alzheimer's disease, there remains substantial " hidden heritability." It is thought that some of this missing heritability may be because of gene-gene, i.e., epistatic, interactions. We examined potential epistasis between 110

Detecting gene-gene interactions or epistasis in studies of human complex diseases is a big challenge in the area of epidemiology. To address this problem, several methods have been developed, mainly in the context of data dimensionality reduction. One of these methods, Model-Based Multifactor Dimensionality Reduction, has so far mainly been applied to case-control studies. In this study, we evaluate the power of Model-Based Multifactor Dimensionality Reduction for quantitative traits to detect gene-gene interactions (epistasis) in the presence of error-free and noisy data. Considered sources of error are genotyping errors, missing genotypes, phenotypic mixtures and genetic heterogeneity. Our simulation study encompasses a variety of settings with varying minor allele frequencies and genetic variance for different epistasis models. On each simulated data, we have performed Model-Based Multifactor Dimensionality Reduction in two ways: with and without adjustment for main effects of (known) functional SNPs. In line with binary trait counterparts, our simulations show that the power is lowest in the presence of phenotypic mixtures or genetic heterogeneity compared to scenarios with missing genotypes or genotyping errors. In addition, empirical power estimates reduce even further with main effects corrections, but at the same time, false-positive percentages are reduced as well. In conclusion, phenotypic mixtures and genetic heterogeneity remain challenging for epistasis detection, and careful thought must be given to the way important lower-order effects are accounted for in the analysis.

To investigate the genetic component of multifactorial diseases such as type 1 (insulin-dependent) diabetes mellitus (IDDM), models involving the joint action of several disease loci are important. These models can give increased power to detect an effect and a greater understanding of etiological mechanisms. Here, we present an extension of the maximum lod score method of N. Risch, which allows the simultaneous detection and modeling of two unlinked disease loci. Genetic constraints on the identical-by-descent sharing probabilities, analogous to the {open_quotes}triangle{close_quotes} restrictions in the single-locus method, are derived, and the size and power of the test statistics are investigated. The method is applied to affected-sib-pair data, and the joint effects of IDDM1 (HLA) and IDDM2 (the INS VNTR) and of IDDM1 and IDDM4 (FGF3-linked) are assessed with relation to the development of IDDM. In the presence of genetic heterogeneity, there is seen to be a significant advantage in analyzing more than one locus simultaneously. Analysis of these families indicates that the effects at IDDM1 and IDDM2 are well described by a multiplicative genetic model, while those at IDDM1 and IDDM4 follow a heterogeneity model. 17 refs., 9 tabs.

Full Text Available Although oxytocin (OT has become a major target for the investigation of positive social processes, it can be assumed that it exerts its effects in concert with other neurotransmitters. One candidate for such an interaction is dopamine (DA. For both systems, genetic variants have been identified that influence the availability of the particular substance. A variant of the gene coding for the transmembrane protein CD38 (rs3796863, which is engaged in OT secretion, has been associated with OT plasma level. The common catechol-O-methyltransferase (COMT val158met polymorphism is known to influence COMT activity and therefore the degradation of DA. The present study aimed to investigate OTxDA interactions in the context of an OT challenge study. Hence, we tested the influence of the above mentioned genetic variants and their interaction on the activation of different brain regions (amygdala, VTA, ventral striatum and fusiform gyrus during the presentation of social stimuli. In a pharmacological cross-over design 55 participants were investigated under OT and placebo (PLA by means of fMRI.Brain imaging results revealed no significant effects for VTA or ventral striatum. Regarding the fusiform gyrus, we could not find any effects apart from those already described in (Sauer et al., 2012. Analyses of amygdala activation resulted in no gene main effect, no gene x substance interaction but a significant gene x gene x substance interaction. While under PLA the effect of CD38 on bilateral amygdala activation to social stimuli was modulated by the COMT genotype, no such epistasis effect was found under OT. Our results provide evidence for an OTxDA interaction during responses to social stimuli. We postulate that the effect of central OT secretion on amygdala response is modulated by the availability of DA. Therefore, for an understanding of the effect of social hormones on social behavior, interactions of OT with other transmitter systems have to be taken

Full Text Available Abstract Background Epistasis is recognized as a fundamental part of the genetic architecture of individuals. Several computational approaches have been developed to model gene-gene interactions in case-control studies, however, none of them is suitable for time-dependent analysis. Herein we introduce the Survival Dimensionality Reduction (SDR algorithm, a non-parametric method specifically designed to detect epistasis in lifetime datasets. Results The algorithm requires neither specification about the underlying survival distribution nor about the underlying interaction model and proved satisfactorily powerful to detect a set of causative genes in synthetic epistatic lifetime datasets with a limited number of samples and high degree of right-censorship (up to 70%. The SDR method was then applied to a series of 386 Dutch patients with active rheumatoid arthritis that were treated with anti-TNF biological agents. Among a set of 39 candidate genes, none of which showed a detectable marginal effect on anti-TNF responses, the SDR algorithm did find that the rs1801274 SNP in the FcγRIIa gene and the rs10954213 SNP in the IRF5 gene non-linearly interact to predict clinical remission after anti-TNF biologicals. Conclusions Simulation studies and application in a real-world setting support the capability of the SDR algorithm to model epistatic interactions in candidate-genes studies in presence of right-censored data. Availability: http://sourceforge.net/projects/sdrproject/

Epistasis is recognized as a fundamental part of the genetic architecture of individuals. Several computational approaches have been developed to model gene-gene interactions in case-control studies, however, none of them is suitable for time-dependent analysis. Herein we introduce the Survival Dimensionality Reduction (SDR) algorithm, a non-parametric method specifically designed to detect epistasis in lifetime datasets. The algorithm requires neither specification about the underlying survival distribution nor about the underlying interaction model and proved satisfactorily powerful to detect a set of causative genes in synthetic epistatic lifetime datasets with a limited number of samples and high degree of right-censorship (up to 70%). The SDR method was then applied to a series of 386 Dutch patients with active rheumatoid arthritis that were treated with anti-TNF biological agents. Among a set of 39 candidate genes, none of which showed a detectable marginal effect on anti-TNF responses, the SDR algorithm did find that the rs1801274 SNP in the Fc gamma RIIa gene and the rs10954213 SNP in the IRF5 gene non-linearly interact to predict clinical remission after anti-TNF biologicals. Simulation studies and application in a real-world setting support the capability of the SDR algorithm to model epistatic interactions in candidate-genes studies in presence of right-censored data. http://sourceforge.net/projects/sdrproject/.

Background Epistasis is recognized as a fundamental part of the genetic architecture of individuals. Several computational approaches have been developed to model gene-gene interactions in case-control studies, however, none of them is suitable for time-dependent analysis. Herein we introduce the Survival Dimensionality Reduction (SDR) algorithm, a non-parametric method specifically designed to detect epistasis in lifetime datasets. Results The algorithm requires neither specification about the underlying survival distribution nor about the underlying interaction model and proved satisfactorily powerful to detect a set of causative genes in synthetic epistatic lifetime datasets with a limited number of samples and high degree of right-censorship (up to 70%). The SDR method was then applied to a series of 386 Dutch patients with active rheumatoid arthritis that were treated with anti-TNF biological agents. Among a set of 39 candidate genes, none of which showed a detectable marginal effect on anti-TNF responses, the SDR algorithm did find that the rs1801274 SNP in the FcγRIIa gene and the rs10954213 SNP in the IRF5 gene non-linearly interact to predict clinical remission after anti-TNF biologicals. Conclusions Simulation studies and application in a real-world setting support the capability of the SDR algorithm to model epistatic interactions in candidate-genes studies in presence of right-censored data. Availability: http://sourceforge.net/projects/sdrproject/ PMID:20691091

The etiology of common human disease often involves a complex genetic architecture, where numerous points of genetic variation interact to influence disease susceptibility. Automating the detection of such epistatic genetic risk factors poses a major computational challenge, as the number of possible gene-gene interactions increases combinatorially with the number of sequence variations. Previously, we addressed this challenge with the development of a computational evolution system (CES) that incorporates greater biological realism than traditional artificial evolution methods. Our results demonstrated that CES is capable of efficiently navigating these large and rugged epistatic landscapes toward the discovery of biologically meaningful genetic models of disease predisposition. Further, we have shown that the efficacy of CES is improved dramatically when the system is provided with statistical expert knowledge. We anticipate that biological expert knowledge, such as genetic regulatory or protein-protein interaction maps, will provide complementary information, and further improve the ability of CES to model the genetic architectures of common human disease. The goal of this study is to test this hypothesis, utilizing publicly available protein-protein interaction information. We show that by incorporating this source of expert knowledge, the system is able to identify functional interactions that represent more concise models of disease susceptibility with improved accuracy. Our ability to incorporate biological knowledge into learning algorithms is an essential step toward the routine use of methods such as CES for identifying genetic risk factors for common human diseases.

Fanconi anemia (FA) is a heritable disease characterized by bone marrow failure, congenital abnormalities, and cancer predisposition. The 15 identified FA genes operate in a molecular pathway to preserve genomic integrity. Within this pathway the FA core complex operates as an ubiquitin ligase that activates the complex of FANCD2 and FANCI to coordinate DNA repair. The FA core complex is formed by at least 12 proteins. However, only the FANCL subunit displays ubiquitin ligase activity. FANCA and FANCG are members of the FA core complex for which no other functions have been described than to participate in protein interactions. In this study we generated mice with combined null alleles for Fanca and Fancg to identify extended functions for these genes by characterizing the double mutant mice and cells. Double mutant a(-/-)/g(-/-) mice were born at near Mendelian frequencies without apparent developmental abnormalities. Histological analysis of a(-/-)/g(-/-) mice revealed a Leydig cell hyperplasia and frequent vacuolization of Sertoli cells in testes, while ovaries were depleted from developing follicles and displayed an interstitial cell hyperplasia. These gonadal aberrations were associated with a compromised fertility of a(-/-)/g(-/-) males and females. During the first year of life a(-/-)/g(-/-) did not develop malignancies or bone marrow failure. At the cellular level a(-/-)/g(-/-), Fanca(-/-), and Fancg(-/-) cells proved equally compromised in DNA crosslink and homology-directed repair. Overall the phenotype of a(-/-)/g(-/-) double knockout mice and cells appeared highly similar to the phenotype of Fanca or Fancg single knockouts. The lack of an augmented phenotype suggest that null mutations in Fanca or Fancg are fully epistatic, making additional important functions outside of the FA core complex highly unlikely. 2011 Elsevier B.V. All rights reserved.

Full Text Available Biological systems produce phenotypes that appear to be robust to perturbation by mutations and environmental variation. Prior studies identified genes that, when impaired, reveal previously cryptic genetic variation. This result is typically interpreted as evidence that the disrupted gene normally increases robustness to mutations, as such robustness would allow cryptic variants to accumulate. However, revelation of cryptic genetic variation is not necessarily evidence that a mutationally robust state has been made less robust. Demonstrating a difference in robustness requires comparing the ability of each state (with the gene perturbed or intact to suppress the effects of new mutations. Previous studies used strains in which the existing genetic variation had been filtered by selection. Here, we use mutation accumulation (MA lines that have experienced minimal selection, to test the ability of histone H2A.Z (HTZ1 to increase robustness to mutations in the yeast Saccharomyces cerevisiae. HTZ1, a regulator of chromatin structure and gene expression, represents a class of genes implicated in mutational robustness. It had previously been shown to increase robustness of yeast cell morphology to fluctuations in the external or internal microenvironment. We measured morphological variation within and among 79 MA lines with and without HTZ1. Analysis of within-line variation confirms that HTZ1 increases microenvironmental robustness. Analysis of between-line variation shows the morphological effects of eliminating HTZ1 to be highly dependent on the line, which implies that HTZ1 interacts with mutations that have accumulated in the lines. However, lines without HTZ1 are, as a group, not more phenotypically diverse than lines with HTZ1 present. The presence of HTZ1, therefore, does not confer greater robustness to mutations than its absence. Our results provide experimental evidence that revelation of cryptic genetic variation cannot be assumed to be

Biological systems produce phenotypes that appear to be robust to perturbation by mutations and environmental variation. Prior studies identified genes that, when impaired, reveal previously cryptic genetic variation. This result is typically interpreted as evidence that the disrupted gene normally increases robustness to mutations, as such robustness would allow cryptic variants to accumulate. However, revelation of cryptic genetic variation is not necessarily evidence that a mutationally robust state has been made less robust. Demonstrating a difference in robustness requires comparing the ability of each state (with the gene perturbed or intact) to suppress the effects of new mutations. Previous studies used strains in which the existing genetic variation had been filtered by selection. Here, we use mutation accumulation (MA) lines that have experienced minimal selection, to test the ability of histone H2A.Z (HTZ1) to increase robustness to mutations in the yeast Saccharomyces cerevisiae. HTZ1, a regulator of chromatin structure and gene expression, represents a class of genes implicated in mutational robustness. It had previously been shown to increase robustness of yeast cell morphology to fluctuations in the external or internal microenvironment. We measured morphological variation within and among 79 MA lines with and without HTZ1. Analysis of within-line variation confirms that HTZ1 increases microenvironmental robustness. Analysis of between-line variation shows the morphological effects of eliminating HTZ1 to be highly dependent on the line, which implies that HTZ1 interacts with mutations that have accumulated in the lines. However, lines without HTZ1 are, as a group, not more phenotypically diverse than lines with HTZ1 present. The presence of HTZ1, therefore, does not confer greater robustness to mutations than its absence. Our results provide experimental evidence that revelation of cryptic genetic variation cannot be assumed to be caused by loss of

Genetic interactions, or non-additive effects between genes, play a crucial role in many cellular processes and disease. Which mechanisms underlie these genetic interactions has hardly been characterized. Understanding the molecular basis of genetic interactions is crucial in deciphering pathway organization and understanding the relationship between genotype, phenotype and disease. To investigate the nature of genetic interactions between gene-specific transcription factors (GSTFs) in Saccharomyces cerevisiae, we systematically analyzed 72 GSTF pairs by gene expression profiling double and single deletion mutants. These pairs were selected through previously published growth-based genetic interactions as well as through similarity in DNA binding properties. The result is a high-resolution atlas of gene expression-based genetic interactions that provides systems-level insight into GSTF epistasis. The atlas confirms known genetic interactions and exposes new ones. Importantly, the data can be used to investigate mechanisms that underlie individual genetic interactions. Two molecular mechanisms are proposed, "buffering by induced dependency" and "alleviation by derepression". These mechanisms indicate how negative genetic interactions can occur between seemingly unrelated parallel pathways and how positive genetic interactions can indirectly expose parallel rather than same-pathway relationships. The focus on GSTFs is important for understanding the transcription regulatory network of yeast as it uncovers details behind many redundancy relationships, some of which are completely new. In addition, the study provides general insight into the complex nature of epistasis and proposes mechanistic models for genetic interactions, the majority of which do not fall into easily recognizable within- or between-pathway relationships.

Three flint and three dent maize (Zea mays L.) inbred lines, their possible F1 crosses, F2 and backcross progenies, and all possible three-way crosses were evaluated in a three-year experiment for yield, ear moisture, and plant height. The purpose was to estimate genetic parameters in European breeding materials from (i) generation means analysis, (ii) diallel analysis of generation means, and (iii) analysis of F1 and three-way cross hybrids. Method (i) was based on the F∞-metric model and methods (ii) and (iii) on the Eberhart-Gardner (1966) genetic model; both models extended for heterotic maternal effects.Differences among generation means for yield and plant height were mainly attributable to dominance effects. Epistatic effects were significantly different from zero in a few crosses and considerably reduced heterosis in both traits. Additive x additive and domiance x dominance effects for yield were consistently positive and negative, respectively. Significant maternal effects were established to the advantage of generations with a heterozygous seed parent. In the diallel analysis, mean squares for dominance effects were greater than for additive effects for yield and plant height but smaller for ear moisture. Though significant for yield and plant height, epistatic variation was small compared to additive and dominance variation. Estimates of additive x additive epistasis for yield were significantly negative in 11 of 15 crosses, suggesting that advantageous gene combinations in the lines had been disrupted by recombination in the segregating generations. The analysis of hybrids supported the above findings regarding the analysis of variance. However, the estimates of additive x additive epistasis for yield were considerably smaller and only minimally correlated with those from the diallel analysis. Use of noninbred materials as opposed to materials with different levels of inbreeding is considered the main reason for the discrepancies in the results.

Most of these notes were presented as part of a two-quarter course on theoretical population genetics at The University of Chicago. Almost all the students were either undergraduates in mathematics or graduate students in the biological sciences. The only prerequisites were calculus and matrices. As is done in these notes, biological background and additional mathematical techniques were covered when they were required. I have included the relevant problems assigned in the course. My aim in these notes is to formulate the various models fairly generally, making the biological assumptions quite explicit, and to perform the analyses relatively rigorously. I hope the choice and treatment of topics will enable the reader to understand and evaluate detailed analyses of specific models and applications in the literature. No attempt has been made to review the literature or to assign credit. Most of the references are to papers directly germane to the subjects and approaches covered here. Frequency of reference is n...

, and social cognition. RESULTS: Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1% to 3% of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype...... psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2% using the polygenic score only to 4...... additional variation above and beyond that explained by the polygenic score. DESIGN, SETTING, AND PARTICIPANTS: Patients with psychosis (n = 424) were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition. We used the Psychiatric GWAS...

The Csr global regulatory system coordinates gene expression in response to metabolic status. This system utilizes the RNA binding protein CsrA to regulate gene expression by binding to transcripts of structural and regulatory genes, thus affecting their structure, stability, translation, and/or transcription elongation. CsrA activity is controlled by sRNAs, CsrB and CsrC, which sequester CsrA away from other transcripts. CsrB/C levels are partly determined by their rates of turnover, which requires CsrD to render them susceptible to RNase E cleavage. Previous epistasis analysis suggested that CsrD affects gene expression through the other Csr components, CsrB/C and CsrA. However, those conclusions were based on a limited analysis of reporters. Here, we reassessed the global behavior of the Csr circuitry using epistasis analysis with RNA seq (Epi-seq). Because CsrD effects on mRNA levels were entirely lost in the csrA mutant and largely eliminated in a csrB/C mutant under our experimental conditions, while the majority of CsrA effects persisted in the absence of csrD, the original model accounts for the global behavior of the Csr system. Our present results also reflect a more nuanced role of CsrA as terminal regulator of the Csr system than has been recognized.

Addiction is a complex, multi-factorial disease, and thus, analyzing genetic variants at multiple loci and gene-gene interactions among them (epistasis) can provide crucial clues about causative factors of addiction which cannot be detected with single-nucleotide polymorphism (SNP) association studies. In this study, we discuss the interaction between the 1359 G/A polymorphism of the CNR1 gene and the DRD2 gene polymorphisms and the net effect of any possible epistasis on the cannabis addiction phenotype in a Turkish population. Using bivariate synergy and mutual information concepts as a means of capturing the magnitude of interaction between marker pairs, the present study not only confirms the A1 marker allele as a risk factor but also reveals a finer-grained association between A and B markers which manifests itself both as a preventive and a risk factor. Our results indicate that the increased phenotype of cases require an individual to be either heterozygous at both loci or homozygous at locus B with homozygous risk factor A1A1 present. We hypothesize that overlapping expressions of CB1 and D2R is the cause of CB1-D2R interactions in cases of substance abuse and the different polymorphisms of CNR1 and DRD2 genes may have decisive roles in the nature of these interactions in terms of promoting or alleviating the cannabis addiction risk factor of the individual.

Full Text Available African Americans have a disproportionate risk for developing nephropathy. This disparity has been attributed to coding variants (G1 and G2 in apolipoprotein L1 (APOL1; however, there is little functional evidence supporting the role of this protein in renal function. Here, we combined genetics and in vivo modeling to examine the role of apol1 in glomerular development and pronephric filtration and to test the pathogenic potential of APOL1 G1 and G2. Translational suppression or CRISPR/Cas9 genome editing of apol1 in zebrafish embryos results in podocyte loss and glomerular filtration defects. Complementation of apol1 morphants with wild-type human APOL1 mRNA rescues these defects. However, the APOL1 G1 risk allele does not ameliorate defects caused by apol1 suppression and the pathogenicity is conferred by the cis effect of both individual variants of the G1 risk haplotype (I384M/S342G. In vivo complementation studies of the G2 risk allele also indicate that the variant is deleterious to protein function. Moreover, APOL1 G2, but not G1, expression alone promotes developmental kidney defects, suggesting a possible dominant-negative effect of the altered protein. In sickle cell disease (SCD patients, we reported previously a genetic interaction between APOL1 and MYH9. Testing this interaction in vivo by co-suppressing both transcripts yielded no additive effects. However, upon genetic or chemical induction of anemia, we observed a significantly exacerbated nephropathy phenotype. Furthermore, concordant with the genetic interaction observed in SCD patients, APOL1 G2 reduces myh9 expression in vivo, suggesting a possible interaction between the altered APOL1 and myh9. Our data indicate a critical role for APOL1 in renal function that is compromised by nephropathy-risk encoding variants. Moreover, our interaction studies indicate that the MYH9 locus is also relevant to the phenotype in a stressed microenvironment and suggest that consideration of

Multifactor Dimensionality Reduction (MDR) is a popular and successful data mining method developed to characterize and detect nonlinear complex gene-gene interactions (epistasis) that are associated with disease susceptibility. Because MDR uses a combinatorial search strategy to detect interaction, several filtration techniques have been developed to remove genes (SNPs) that have no interactive effects prior to analysis. However, the cutoff values implemented for these filtration methods are arbitrary, therefore different choices of cutoff values will lead to different selections of genes (SNPs). We suggest incorporating a global test of p-values to filtration procedures to identify the optimal number of genes/SNPs for further MDR analysis and demonstrate this approach using a ReliefF filter technique. We compare the performance of different global testing procedures in this context, including the Kolmogorov-Smirnov test, the inverse chi-square test, the inverse normal test, the logit test, the Wilcoxon test and Tippett's test. Additionally we demonstrate the approach on a real data application with a candidate gene study of drug response in Juvenile Idiopathic Arthritis. Extensive simulation of correlated p-values show that the inverse chi-square test is the most appropriate approach to be incorporated with the screening approach to determine the optimal number of SNPs for the final MDR analysis. The Kolmogorov-Smirnov test has high inflation of Type I errors when p-values are highly correlated or when p-values peak near the center of histogram. Tippett's test has very low power when the effect size of GxG interactions is small. The proposed global tests can serve as a screening approach prior to individual tests to prevent false discovery. Strong power in small sample sizes and well controlled Type I error in absence of GxG interactions make global tests highly recommended in epistasis studies.

Full Text Available Abstract Background Multifactor Dimensionality Reduction (MDR is a popular and successful data mining method developed to characterize and detect nonlinear complex gene-gene interactions (epistasis that are associated with disease susceptibility. Because MDR uses a combinatorial search strategy to detect interaction, several filtration techniques have been developed to remove genes (SNPs that have no interactive effects prior to analysis. However, the cutoff values implemented for these filtration methods are arbitrary, therefore different choices of cutoff values will lead to different selections of genes (SNPs. Methods We suggest incorporating a global test of p-values to filtration procedures to identify the optimal number of genes/SNPs for further MDR analysis and demonstrate this approach using a ReliefF filter technique. We compare the performance of different global testing procedures in this context, including the Kolmogorov-Smirnov test, the inverse chi-square test, the inverse normal test, the logit test, the Wilcoxon test and Tippett’s test. Additionally we demonstrate the approach on a real data application with a candidate gene study of drug response in Juvenile Idiopathic Arthritis. Results Extensive simulation of correlated p-values show that the inverse chi-square test is the most appropriate approach to be incorporated with the screening approach to determine the optimal number of SNPs for the final MDR analysis. The Kolmogorov-Smirnov test has high inflation of Type I errors when p-values are highly correlated or when p-values peak near the center of histogram. Tippett’s test has very low power when the effect size of GxG interactions is small. Conclusions The proposed global tests can serve as a screening approach prior to individual tests to prevent false discovery. Strong power in small sample sizes and well controlled Type I error in absence of GxG interactions make global tests highly recommended in epistasis studies.

We conducted a simultaneous analysis of candidate genetic loci for their genotypic association with the susceptibility to vascular dementia (VaD) to put forth the best model for predicting genetic susceptibility to VaD. Individual-locus effects and their epistatic effects on susceptibility to VaD were simultaneously assessed by multifactor dimensionality reduction and entropy-based method. The 23 loci in 12 genes were studied in 207 VaD patients and age-matched and sex-matched 207 controls. The multifactor dimensionality reduction analysis revealed that the best single-locus candidate model included angiotensinogen (AGT) Thr235Met with testing accuracy (TA) of 58.31%, the best two-locus candidate model included AGT Thr235Met and transforming growth factor-beta1 Pro10Leu with TA of 58.06%, the best three-locus candidate model was not significant (P>0.05), and the best four-locus candidate model included transforming growth factor-beta1 Pro10Leu, AGT Thr235Met, sterol regulatory element binding protein 2 G34995T, and leukemia inhibitory factor T4524G with TA of 57.13% (P<0.05). The best four-locus model was, however, still in question because of the inconsistent best model selection by cross-validation. Synergistic epistatic effect of the best two-locus model was proven by entropy-based estimation. The best predictor for genetic susceptibility to VaD was the single-locus model of AGT. The best two-locus model reflecting epistasis would be also employed for predicting its susceptibility. Further studies on the epistasis are to elucidate their underlying mechanisms.

Genotypes of two different loci of the Pneumocystis jirovecii mitochondrial gene were studied in specimens from a total of 75 Pneumocystis pneumonia patients in Spain, France and Cuba. A new genotype of the mitochondrial small subunit rRNA gene of P. jirovecii (160A/196T) was identified, which was revealed to be the most common in these three countries, especially in Cuba where its proportion reached 93.8%. Our data imply that the new genotype might be circulating worldwide and also suggests that the distribution of P. jirovecii genotypes could be narrower in islands such as Cuba.

inequality constraints. Such a constrained optimization prob- lem is well within the capabilities of freely available, easy-to- use constrained optimizers, for instance the standard routine. constrOptim in R (R Core Team 2014). The method used by constrOptim to impose the constraints is the addi- tion of a logarithmic barrier to ...

Full Text Available Epistasis that may explain a large portion of the phenotypic variation for complex economic traits of animals has been ignored in many genetic association studies. A Baysian method was introduced to draw inferences about multilocus genotypic effects based on their marginal posterior distributions by a Gibbs sampler. A simulation study was conducted to provide statistical powers under various unbalanced designs by using this method. Data were simulated by combined designs of number of loci, within genotype variance, and sample size in unbalanced designs with or without null combined genotype cells. Mean empirical statistical power was estimated for testing posterior mean estimate of combined genotype effect. A practical example for obtaining empirical statistical power estimates with a given sample size was provided under unbalanced designs. The empirical statistical powers would be useful for determining an optimal design when interactive associations of multiple loci with complex phenotypes were examined.

Full Text Available Aims. Epistasis from gene set based on the function-related genes may confer to the susceptibility of type 2 diabetes (T2D. The Wnt pathway has been reported to play an important role in the pathogenesis of T2D. Here we applied tag SNPs to explore the association between epistasis among genes from Wnt and T2D in the Han Chinese population. Methods. Variants of fourteen genes selected from Wnt pathways were performed to analyze epistasis. Gene–gene interactions in case-control samples were identified by generalized multifactor dimensionality reduction (GMDR method. We performed a case-controlled association analysis on a total of 1,026 individual with T2D and 1,157 controls via tag SNPs in Wnt pathway. Results. In single-locus analysis, SNPs in four genes were significantly associated with T2D adjusted for multiple testing (rs7903146C in TCF7L2, p = 3.21∗10−3, OR = 1.39, 95% CI [1.31–1.47], rs12904944G in SMAD3, p = 2.51∗10−3, OR = 1.39, 95% CI [1.31–1.47], rs2273368C in WNT2B, p = 4.46∗10−3, OR = 1.23, 95% CI [1.11–1.32], rs6902123C in PPARD, p = 1.14∗10−2, OR = 1.40, 95% CI [1.32–1.48]. The haplotype TGC constructed by TCF7L2 (rs7903146, DKK1 (rs2241529 and BTRC (rs4436485 showed a significant association with T2D (OR = 0.750, 95% CI [0.579–0.972], P = 0.03. For epistasis analysis, the optimized combination was the twolocus model of WNT2B rs2273368 and TCF7L2rs7903146, which had the maximum cross-validation consistency. This was 9 out of 10 for the sign test at 0.0107 level. The best combination increased the risk of T2D by 1.47 times (95% CI [1.13–1.91], p = 0.0039. Conclusions. Epistasis between TCF7L2 and WNT2B is associated with the susceptibility of T2D in a Han Chinese population. Our results were compatible with the idea of the complex nature of T2D that would have been missed using conventional tools.

Improvements in the usefulness of QTL analysis arise from better statistical methods applied to the problem, ability to analyze more complex mating designs, and the fitting of less simplified genetic models. Here we review the advantages of different plant mating designs in QTL analysis and conclude that diallel designs have several favorable properties. We then turn to the detection of systematic genome-wide synergistic epistasis. This form of epistasis has important implications from evolutionary (maintenance of sexual reproduction and concealment of cryptic genetic variation) and practical perspectives (response to pyramided favorable alleles). We develop two methods for detecting systematic synergistic epistasis, one based on analyzing interactions between locus effects and predicted individual genotypic values and one based on analyzing pairwise locus interactions. Using the first method we detect synergistic epistasis in a barley and a wheat dataset but not in a maize dataset. We fail to detect synergistic epistasis with the second method. We discuss our results in the light of theoretical questions concerning the mechanisms of synergistic epistasis.

Full Text Available Atrazine chlorohydrolase (AtzA and its close relative melamine deaminase (TriA differ by just nine amino acid substitutions but have distinct catalytic activities. Together, they offer an informative model system to study the molecular processes that underpin the emergence of new enzymatic function. Here we have constructed the potential evolutionary trajectories between AtzA and TriA, and characterized the catalytic activities and biophysical properties of the intermediates along those trajectories. The order in which the nine amino acid substitutions that separate the enzymes could be introduced to either enzyme, while maintaining significant catalytic activity, was dictated by epistatic interactions, principally between three amino acids within the active site: namely, S331C, N328D and F84L. The mechanistic basis for the epistatic relationships is consistent with a model for the catalytic mechanisms in which protonation is required for hydrolysis of melamine, but not atrazine.

This test plan is a document that provides a systematic approach to the planned testing of rooftop structures to determine their actual load carrying capacity. This document identifies typical tests to be performed, the responsible parties for testing, the general feature of the tests, the testing approach, test deliverables, testing schedule, monitoring requirements, and environmental and safety compliance.

... you want to learn. Search form Search Predictive testing You are here Home Testing & Services Testing for ... you make the decision. What Is Predictive Genetic Testing Predictive genetic testing searches for genetic changes, or ...

Presents articles on test anxiety, personality tests, history of tests and benefits to be derived from their use, tests as tools in career decision-making, temperament needs for certain jobs (as determined by personality tests), interest inventories, testing exceptional students, and testing to evaluate vocational needs of special needs groups.…

Direct antiglobulin test; Indirect antiglobulin test; Anemia - hemolytic ... No special preparation is necessary for this test. ... There are 2 types of the Coombs test: Direct Indirect The direct ... that are stuck to the surface of red blood cells. Many diseases ...

... Safe Videos for Educators Search English Español Test Anxiety KidsHealth / For Teens / Test Anxiety What's in this ... with their concentration or performance. What Is Test Anxiety? Test anxiety is actually a type of performance ...

... Urinary Tract Imaging Urodynamic Testing Virtual Colonoscopy Urodynamic Testing What is the urinary tract? The urinary tract ... view of the urinary tract What is urodynamic testing? Urodynamic testing is any procedure that looks at ...

Duodenal parasites test; Giardia - string test ... To have this test, you swallow a string with a weighted gelatin capsule on the end. The string is pulled out 4 hours later. Any bile , blood, or mucus attached to ...

Laboratory tests check a sample of your blood, urine, or body tissues. A technician or your doctor ... compare your results to results from previous tests. Laboratory tests are often part of a routine checkup ...

... Library ▸ Allergy Library ▸ Allergy testing TTR Share | Allergy Testing If you have an allergy, your immune system ... to avoid contact with the pet if allergy testing shows an allergy to dust mites but not ...

Oxyuriasis test; Enterobiasis test; Tape test ... When a person has a pinworm infection, adult pinworms live in the intestine and colon. At night, the female adult worms deposit their eggs outside the rectum ...

A test chamber for measuring electromagnetic radiation emitted by an apparatus to be tested or for exposing an apparatus to be tested to an electromagnetic radiation field. The test chamber includes a reverberation chamber made of a conductive tent fabric. To create a statistically uniform field in

A test chamber for measuring electromagnetic radiation emitted by an apparatus to be tested or for exposing an apparatus to be tested to an electromagnetic radiation field. The test chamber includes a reverberation chamber made of a conductive tent fabric. To create a statistically uniform field in

A complete guide to the uniaxial tensile test, the cornerstone test for determining the mechanical properties of materials: Learn ways to predict material behavior through tensile testing. Learn how to test metals, alloys, composites, ceramics, and plastics to determine strength, ductility and elastic/plastic deformation. A must for laboratory managers, technicians, materials and design engineers, and students involved with uniaxial tensile testing. Tensile Testing , Second Edition begins with an introduction and overview of the test, with clear explanations of how materials properties are determined from test results. Subsequent sections illustrate how knowledge gained through tensile tests, such as tension properties to predict the behavior (including strength, ductility, elastic or plastic deformation, tensile and yield strengths) have resulted in improvements in materals applications. The Second Edition is completely revised and updated. It includes expanded coverage throughout the volume on a variety of ...

A survey conducted by the American Management Association on workplace-testing policies included questions about drug testing, polygraphs, and testing for the human immunodeficiency virus. The survey found that testing increased from 21 percent in 1986 to 37 percent in 1987 and 48 percent in the 1988 survey. (JOW)

This document discusses inservice testing of safety-related components at nuclear power plants which is performed under the American Society of Mechanical Engineers Boiler and Pressure Vessel Code (the Code). Subsections IWP and IWV of Section XI of the Code state test method and frequency requirements for pumps and valves respectively. Tests vary greatly in quality and frequency. This paper explores the concept of test quality and its relationship with operational readiness and preventive maintenance. This paper also considers the frequencies of component testing. Test quality is related to a test's ability to detect degradation that can cause component failure. The quality of the test depends on several factors, including specific parameters measured, system or component conditions, and instrument accuracy. The quality of some currently required tests for check valves, motor-operated valves, and pumps is also discussed. Suggestions are made to improve test quality by measuring different parameters, testing valves under load, and testing positive displacement pumps at high pressure and centrifugal pumps at high flow rate conditions. These suggestions can help to improve the level of assurance of component operational readiness gained from testing

Inservice testing of safety-related components at nuclear power plants is performed under the American Society of Mechanical Engineers Boiler and Pressure Vessel Code (the Code). Subsections IWP and IWV of Section 11 of the Code state test method and frequency requirements for pumps and valves, respectively. Tests vary greatly in quality and frequency. This paper explores the concept of test quality and its relationship with operational readiness and preventive maintenance. This paper also considers the frequencies of component testing. Test quality is related to a test's ability to detect degradation that can cause component failure. The quality of the test depends on several factors, including specific parameters measured, system or component conditions, and instrument accuracy. The quality of some currently required tests for check valves, motor-operated valves, and pumps is also discussed. Suggestions are made to improve test quality by measuring different parameters, testing valves under load, and testing positive displacement pumps at high pressure and centrifugal pumps at high flow rate conditions. These suggestions can help to improve the level of assurance of component operational readiness gained from testing

... Content View Sources Ask Us Also Known As ACT Activated Coagulation Time Formal Name Activated Clotting Time ... What is being tested? The activated clotting time (ACT) is a test that is used primarily to ...

... on to their children Screening embryos for disease Testing for genetic diseases in adults before they cause ... provide information about the pros and cons of testing. NIH: National Human Genome Research Institute

... normal" values. By comparing your test results with reference values, you and your healthcare provider can see if ... along with other iron tests , when a routine complete blood count (CBC) shows that a person's hemoglobin and hematocrit ...

.... This book provides all the necessary theory and practical guidelines, such as instructions for writing computer programs, to permit experimenters to transform any statistical test into a distribution-free test...

... you have liver or kidney disease . Serum protein electrophoresis. This blood test measures gamma globulins and other ... myeloma. Other names for globulin tests: Serum globulin electrophoresis, total protein What is it used for? Globulin ...

There has been extensive literature on modeling gene-gene interaction (GGI) and gene-environment interaction (GEI) in case-control studies with limited literature on statistical methods for GGI and GEI in longitudinal cohort studies. We borrow ideas from the classical two-way analysis of variance (ANOVA) literature to address the issue of robust modeling of interactions in repeated-measures studies. While classical interaction models proposed by Tukey and Mandel have interaction structures as a function of main effects, a newer class of models, additive main effects and multiplicative interaction (AMMI) models, do not have similar restrictive assumptions on the interaction structure. AMMI entails a singular value decomposition of the cell residual matrix after fitting the additive main effects and has been shown to perform well across various interaction structures. We consider these models for testing GGI and GEI from two perspectives: likelihood ratio test based on cell means and a regression based approach using individual observations. Simulation results indicate that both approaches for AMMI models lead to valid tests in terms of maintaining the type I error rate, with the regression approach having better power properties. The performance of these models was evaluated across different interaction structures and 12 common epistasis patterns. In summary, AMMI model is robust with respect to misspecified interaction structure and is a useful screening tool for interaction even in the absence of main effects. We use the proposed methods to examine the interplay between the hemochromatosis gene and cumulative lead exposure on pulse pressure in the Normative Aging Study. PMID:23798480

CATALOG NUMBER 4. TITLE (and Subtitle) . TYPE OF REPO RI.O COVERED_ US ARMY TEST AND EVALUATION COMMND TEST OF R&TN CEDURE Final------- SOFWAR TEST...verification, the TECON field activity A should offer to provide this service using the CRWG and the TIWG as vehicles for coordination. 2.2 Algorithm... services and controls the applications programs. Among its many functions are dispatching and scheduling of tasks; allocat- ing and freeing of memory

, destroy the insulation and eventually cause breakdown. It is difficult to make a model of the real-life components that can be used to examine all of these phenomena. Some decisions have to be made on how to approach this problem, how to design a test cell and how the tests should be carried out....... In this paper, four suggestions on test cells are considered....

the insulation and eventually cause breakdown.It is difficult to make a model of the real-life components that can be used to examine all of these phenomena. Some decisions have to be made on how to approach this problem, how to design a test cell and how the tests should be carried out. In this paper, four...... suggestions on test cells are considered....

The paper describes the results of oedometer tests carried out with samples from Eemian fresh-water deposits and the methods used to determine the preconsolidation pressure from the test results. The influence of creep in the material on the apparent preconsolidation pressure is estimated from a ...

The standard test for homogeneity of covariance matrices, known as the Bartlett test, is notoriously sensitive to violations of Gaussian assumptions. Its asymptotic behavior under non-Gaussian densities and its robustification (validity-robustness and efficiency-robustness) have been the subject of

Software testing has become a mandatory process in assuring the software product quality. Hence, test management is needed in order to manage the test activities conducted in the software test life cycle. This paper discusses on the challenges faced in the software test life cycle, and how the test processes and test activities, mainly on test cases creation, test execution, and test reporting is being managed and automated using several test automation tools, i.e. Jira, ...

... are injured, bleeding occurs and a process called hemostasis begins. Small cell fragments called platelets adhere to ... be used to evaluate certain components of the hemostasis system. The PTT and PT tests each evaluate ...

... Syndrome Staph Infections and MRSA Stroke Testicular Cancer Thalassemia Thyroid Cancer Thyroid ... Get Tested? To help evaluate insulin production by the beta cells in the pancreas; to help diagnose the ...

In the 1950s, most of the men who witnessed Britain's nuclear tests at Christmas Island in the Pacific were national servicemen, aged 19 or 20. Some revelled in sun and swimming, some were bored, some were too busy to be bored. How many of the twenty thousand servicemen involved in the tests suspected that they might be exposed to radiation that would reveal itself a generation later in blood and bone cancers, sterility, cataracts, or deformities in their children. The Ministry of Defence insists nobody was in danger. This book tells a different story, in the words of the servicemen, and of their medical reports, about secrets which are no longer Official. It is important not only to the victims of a government's extraordinary reluctance to face up to the tragic consequences of a programme of nuclear tests on Christmas Island and in Australia, but to anyone concerned with the damage that nuclear testing is still doing in the world today. (author)

... later stages of the infection. Some conditions may cause a false-positive test, including: IV drug use Lyme disease Certain types of pneumonia Malaria Pregnancy Systemic lupus erythematosus and some other autoimmune ...

... vein, most often in your arm or hand venipuncture . How to Prepare for the Test No special ... Guidelines Viewers & Players MedlinePlus Connect for EHRs For Developers U.S. National Library of Medicine 8600 Rockville Pike, ...

The knowledge test is about competing temporal and spatial expressions of the politics of technological development and national prosperity in contemporary society. The discussion is based on literature of national systems of innovation and industrial networks of various sorts. Similarities...

... risk factor for the development of celiac disease, genetic predisposition. Without this factor, it is impossible that the ... with antibody testing in the future. When the genetic predisposition for celiac disease was detected (on Chromosome 6) ...

This paper discusses some simple issues that arise in testing models, with a focus on models for low energy nuclear structure. By way of simplified examples, we illustrate some dangers in blind statistical assessments, pointing out especially the need to include theoretical uncertainties, the danger of over-weighting precise or physically redundant experimental results, the need to assess competing theories with independent and physically sensitive observables, and the value of statistical tests properly evaluated. (paper)

Full Text Available Single-nucleotide polymorphisms (SNPs in inositol 1,4,5-trisphosphate 3-kinase C (ITPKC, rs28493229 and caspase-3 (CASP3, rs113420705 are associated with susceptibility to KD in Japanese and Taiwanese populations. This study was conducted to investigate the involvement of these 2 SNPs in the risk for intravenous immunoglobulin (IVIG resistance and coronary artery lesion (CAL in Taiwanese population. A total of 340 KD patients were subjected to assess by the identification of 2-locus genes model. A combinatorial association between ITPKC (rs28493229 and CASP3 (rs113420705 was found in CAL formation (P = 0.0227, OR: 3.06. KD patients with high-risk genotype had a trend of overrepresentation in IVIG resistance compared with individual SNPs. Our findings suggest the existence of genetic factors affecting patients' risk for CAL formation and IVIG responsiveness in a Taiwanese population.

However, maximal HR was significantly higher in all groups during their sporting activities than during stress testing in the laboratory (P < 0.01). Conclusions. Maximal HR in veteran athletes during specific sporting activities was significantly higher than that attained during a routine sECG. This finding was not sport-specific, ...

Molecular phylogenetic analysis of the genus Allium L. has been mainly based on the nucleotide sequences of ITS region. In 2009 matK and rbcL were accepted as a two-locus DNA barcode to classify plant species by the Consortium for the Barcode of Life (CBOL) Plant Working Group. MatK region has been ...

This report contains theory, procedure technique and interpretation of radiographic examination and written for whom preparing radiographic test Level II. To determine this baseline of technical competence in the examination, the individual must demonstrate a knowledge of radiography physics, radiation safety, technique development, radiation detection and measurement, facility design, and the characteristics of radiation-producing devices and their principles of operation. (author) 98 figs., 23 tabs.

A method for non-destructive testing of an industrial component to ascertain if it is a single crystal, and to find the crystal orientations of those parts of the component which are single crystals, involves irradiating the component with a monochromatic collimated neutron beam. Diffracted neutron beams are observed live by means of LiF/ZnS composite screen, an image intensifier and a television camera and screen. (author)

Coccidioidomycosis antibody test; Coccidioides blood test; Valley fever blood test ... There is no special preparation for the test. ... The precipitin test is one of several tests that can be done to determine if you are infected with coccidioides, which ...

The Test of German as a Foreign Language (TestDaF) plays a critical role as a standardized test of German language proficiency. Developed and administered by the Society for Academic Study Preparation and Test Development (g.a.s.t.), TestDaF was launched in 2001 and has experienced persistent annual growth, with more than 44,000 test takers in…

... to learn. Search form Search Tests related to pregnancy You are here Home Testing & Services Testing for ... to Genetic Counseling . What Are Tests Related to Pregnancy? Pregnancy related testing is done before or during ...

... you want to learn. Search form Search Diagnostic testing You are here Home Testing & Services Testing for ... help you make the decision. What Is Diagnostic Testing? Diagnostic genetic testing can usually work out if ...

One in three people has been infected with Mycobacterium tuberculosis (MTB), and the risk for MTB infection in HIV-infected individuals is even higher. We hypothesized that HIV-positive individuals living in tuberculosis-endemic regions who do not get infected by Mycobacterium tuberculosis are genetically resistant. Using an "experiment of nature" design that proved successful in our previous work, we performed a genome-wide association study of tuberculin skin test positivity using 469 HIV-positive patients from prospective study cohorts of tuberculosis from Tanzania and Uganda to identify genetic loci associated with MTB infection in the context of HIV-infection. Among these individuals, 244 tested were tuberculin skin test (TST) positive either at enrollment or during the >8 year follow up, while 225 were not. We identified a genome-wide significant association between a dominant model of rs877356 and binary TST status in the combined cohort (Odds ratio = 0.2671, p = 1.22x10-8). Association was replicated with similar significance when examining TST induration as a continuous trait. The variant lies in the 5q31.1 region, 57kb downstream from IL9. Two-locus analyses of association of variants near rs877356 showed a haplotype comprised of rs877356 and an IL9 missense variant, rs2069885, had the most significant association (p = 1.59x10-12). We also replicated previously linked loci on chromosomes 2, 5, and 11. IL9 is a cytokine produced by mast cells and TH2 cells during inflammatory responses, providing a possible link between airway inflammation and protection from MTB infection. Our results indicate that studying uninfected, HIV-positive participants with extensive exposure increases the power to detect associations in complex infectious disease.

Learning Software Testing with Test Studio is a practical, hands-on guide that will help you get started with Test Studio to design your automated solution and tests. All through the book, there are best practices and tips and tricks inside Test Studio which can be employed to improve your solution just like an experienced QA.If you are a beginner or a professional QA who is seeking a fast, clear, and direct to the point start in automated software testing inside Test Studio, this book is for you. You should be familiar with the .NET framework, mainly Visual Studio, C#, and SQL, as the book's

The groundbreaking book Design Driven Testing brings sanity back to the software development process by flipping around the concept of Test Driven Development (TDD) - restoring the concept of using testing to verify a design instead of pretending that unit tests are a replacement for design. Anyone who feels that TDD is "Too Damn Difficult" will appreciate this book. Design Driven Testing shows that, by combining a forward-thinking development process with cutting-edge automation, testing can be a finely targeted, business-driven, rewarding effort. In other words, you'll learn how to test

... The stool DNA test is a noninvasive laboratory test that identifies DNA changes in the cells of a stool sample. ... the presence of cancer. If a stool DNA test detects abnormal DNA, additional testing may be used to investigate the ...

... is easier to treat. Blood tests and heart health tests can help find heart diseases or identify ... diseases. There are several different types of heart health tests. Your doctor will decide which test or ...

... page: //medlineplus.gov/ency/article/003561.htm Catecholamine blood test To use the sharing features on this page, ... measured with a urine test than with a blood test. How the Test is Performed A blood sample ...

... test results are not meaningful by themselves. Their meaning comes from comparison to reference ranges. Reference ranges ... to detecting the presence of hCG with different brands of home pregnancy kits. Home tests are sometimes ...

Background: Student's two-sample t test is generally used for comparing the means of two independent samples, for example, two treatment arms. Under the null hypothesis, the t test assumes that the two samples arise from the same normally distributed population with unknown variance. Adequate...... control of the Type I error requires that the normality assumption holds, which is often examined by means of a preliminary Shapiro-Wilk test. The following two-stage procedure is widely accepted: If the preliminary test for normality is not significant, the t test is used; if the preliminary test rejects...... the null hypothesis of normality, a nonparametric test is applied in the main analysis. Methods: Equally sized samples were drawn from exponential, uniform, and normal distributions. The two-sample t test was conducted if either both samples (Strategy I) or the collapsed set of residuals from both samples...

The following subjects were dealt with at the meeting: Testing with vibration loads; Hardness testing; Calibration of test devices and equipment; Test technique for compound materials; Vibration strength testing and expense of experiments; Solving problems in introducing forces into samples and components and process of ambulant materials testing. There are 17 separate abstracts from among 43 lectures. (orig./PW) [de

The Survey of Testing Practices was administered to 470 undergraduate students at Pepperdine University and the Univesity of California Los Angeles. The items concerned testing practices in three or four classes taken the previous term: type of test, test administration, class size, procedures for returning tests, test difficulty, and observed…

As a classroom teacher, Kari Smith realized that traditional objective tests don't always assess what students actually know. But tests are so deeply embedded in the education system that it would be difficult to do away with them entirely. Smith decided to make tests into learning tools. In this article, Smith describes three strategies for…

Genes in the major histocompatibility complex (MHC) encode proteins important in activating antigen-specific immune responses. Alleles at adjacent MHC loci are often in strong linkage disequilibrium; however, little is known about the mechanisms responsible for this linkage disequilibrium. Here we...... report that the human MHC HLA-DR2 haplotype, which predisposes to multiple sclerosis, shows more extensive linkage disequilibrium than other common caucasian HLA haplotypes in the DR region and thus seems likely to have been maintained through positive selection. Characterization of two multiple...

Full Text Available An increased understanding of antitumor immunity is necessary for improving cell-based immunotherapies against human cancers. Here, we investigated the roles of two immune system-expressed microRNAs (miRNAs, miR-155 and miR-146a, in the regulation of antitumor immune responses. Our results indicate that miR-155 promotes and miR-146a inhibits interferon γ (IFNγ responses by T cells and reduces solid tumor growth in vivo. Using a double-knockout (DKO mouse strain deficient in both miR-155 and miR-146a, we have also identified an epistatic relationship between these two miRNAs. DKO mice had defective T cell responses and tumor growth phenotypes similar to miR-155−/− mice. Further analysis of the T cell compartment revealed that miR-155 modulates IFNγ expression through a mechanism involving repression of Ship1. Our work reveals critical roles for miRNAs in the reciprocal regulation of CD4+ and CD8+ T cell-mediated antitumor immunity and demonstrates the dominant nature of miR-155 during its promotion of immune responses.

For most complex traits, results from genome-wide association studies show that the proportion of the phenotypic variance attributable to the additive effects of individual SNPs, that is, the heritability explained by the SNPs, is substantially less than the estimate of heritability obtained by

Apr 21, 2014 ... out a molecular dissection of developmental behaviour of plant height in rice and indicated that the number of QTL detected was different at various measuring stages. Some. QTLs could be detected at all stages and some only at one or several stages. Thus, a larger number of QTLs could be detected on ...

Domestication is a multifaceted evolutionary process, involving changes in individual genes, genetic interactions, and emergent phenotypes. There has been extensive discussion of the phenotypic characteristics of plant domestication, and recent research has started to identify the specific genes and mutational mechanisms that control domestication traits. However, there is an apparent disconnect between the simple genetic architecture described for many crop domestication traits, which should facilitate rapid phenotypic change under selection, and the slow rate of change reported from the archeobotanical record. A possible explanation involves the middle ground between individual genetic changes and their expression during development, where gene-by-gene (epistatic) and gene-by-environment interactions can modify the expression of phenotypes and opportunities for selection. These aspects of genetic architecture have the potential to significantly slow the speed of phenotypic evolution during crop domestication and improvement. Here we examine whether epistatic and gene-by-environment interactions have shaped how domestication traits have evolved. We review available evidence from the literature, and we analyze two domestication-related traits, shattering and flowering time, in a mapping population derived from a cross between domesticated foxtail millet and its wild progenitor. We find that compared with wild progenitor alleles, those favored during domestication often have large phenotypic effects and are relatively insensitive to genetic background and environmental effects. Consistent selection should thus be able to rapidly change traits during domestication. We conclude that if phenotypic evolution was slow during crop domestication, this is more likely due to cultural or historical factors than epistatic or environmental constraints.

Among the tests you perform on web applications, security testing is perhaps the most important, yet it's often the most neglected. The recipes in the Web Security Testing Cookbook demonstrate how developers and testers can check for the most common web security issues, while conducting unit tests, regression tests, or exploratory tests. Unlike ad hoc security assessments, these recipes are repeatable, concise, and systematic-perfect for integrating into your regular test suite.

The Idaho National Laboratory (INL) prepared this generic test plan to provide clients (vendors, end users, program sponsors, etc.) with a sense of the scope and depth of vulnerability testing performed at the INL’s Supervisory Control and Data Acquisition (SCADA) Test Bed and to serve as an example of such a plan. Although this test plan specifically addresses vulnerability testing of systems applied to the energy sector (electric/power transmission and distribution and oil and gas systems), it is generic enough to be applied to control systems used in other critical infrastructures such as the transportation sector, water/waste water sector, or hazardous chemical production facilities. The SCADA Test Bed is established at the INL as a testing environment to evaluate the security vulnerabilities of SCADA systems, energy management systems (EMS), and distributed control systems. It now supports multiple programs sponsored by the U.S. Department of Energy, the U.S. Department of Homeland Security, other government agencies, and private sector clients. This particular test plan applies to testing conducted on a SCADA/EMS provided by a vendor. Before performing detailed vulnerability testing of a SCADA/EMS, an as delivered baseline examination of the system is conducted, to establish a starting point for all-subsequent testing. The series of baseline tests document factory delivered defaults, system configuration, and potential configuration changes to aid in the development of a security plan for in depth vulnerability testing. The baseline test document is provided to the System Provider,a who evaluates the baseline report and provides recommendations to the system configuration to enhance the security profile of the baseline system. Vulnerability testing is then conducted at the SCADA Test Bed, which provides an in-depth security analysis of the Vendor’s system.b a. The term System Provider replaces the name of the company/organization providing the system

A compression test assembly is described which prevents buckling of small diameter rigid specimens undergoing compression testing and permits attachment of extensometers for strain measurements. The test specimen is automatically aligned and laterally supported when compressive force is applied to the end caps and transmitted to the test specimen during testing.

Full Text Available The experimental tests performed to validate a tractor prototype before its production, need a substantial financial and time commitment. The tests could be reduced using accelerated tests able to reproduce on the structural part of the tractor, the same damage produced on the tractor during real life in a reduced time. These tests were usually performed reproducing a particular harsh condition a defined number of times, as for example using a bumpy road on track to carry out the test in any weather condition. Using these procedures the loads applied on the tractor structure are different with respect to those obtained during the real use, with the risk to apply loads hard to find in reality. Recently it has been demonstrated how, using the methodologies designed for cars, it is possible to also expedite the structural tests for tractors. In particular, automotive proving grounds were recently successfully used with tractors to perform accelerated structural tests able to reproduce the real use of the machine with an acceleration factor higher than that obtained with the traditional methods. However, the acceleration factor obtained with a tractor on proving grounds is in any case reduced due to the reduced speed of the tractors with respect to cars. In this context, the goal of the paper is to show the development of a methodology to perform an accelerated structural test on a medium power tractor using a 4 post test rig. In particular, several proving ground testing conditions have been performed to measure the loads on the tractor. The loads obtained were then edited to remove the not damaging portion of signals, and finally the loads obtained were reproduced in a 4 post test rig. The methodology proposed could be a valid alternative to the use of a proving ground to reproduce accelerated structural tests on tractors.

... Stress testing provides information about how your heart works during physical stress. Some heart problems are easier to diagnose when ... Testing Show? Stress testing shows how your heart works during physical stress (exercise) and how healthy your heart is. A ...

... this page: //medlineplus.gov/ency/article/003530.htm Campylobacter serology test To use the sharing features on this page, please enable JavaScript. Campylobacter serology test is a blood test to look ...

... ulcers and many cases of stomach inflammation (chronic gastritis). How the Test is Performed There are several ... treating bleeding, or making sure there is no cancer. Why the Test is Performed Testing is most ...

... test may also be appropriate to investigate the cause of fainting if you've fainted only once, but another ... recommend a tilt table test to evaluate the cause of syncope. A tilt table test may also be recommended ...

... page: //medlineplus.gov/ency/article/003474.htm BUN - blood test To use the sharing features on this page, ... for the Test Many medicines can interfere with blood test results. Your health care provider will tell you ...

... page: https://medlineplus.gov/labtests/chloridebloodtest.html Chloride Blood Test To use the sharing features on this page, please enable JavaScript. What is a Chloride Blood Test? A chloride blood test measures the amount of ...

... page: https://medlineplus.gov/labtests/potassiumbloodtest.html Potassium Blood Test To use the sharing features on this page, please enable JavaScript. What is a Potassium Blood Test? A potassium blood test measures the amount of ...

... page: //medlineplus.gov/ency/article/003372.htm Porphyrins blood test To use the sharing features on this page, ... blood or the urine . This article discusses the blood test. How the Test is Performed A blood sample ...

... page: //medlineplus.gov/ency/article/003698.htm Renin blood test To use the sharing features on this page, ... renin test measures the level of renin in blood. How the Test is Performed A blood sample is needed . How ...

... page: //medlineplus.gov/ency/article/003718.htm Prolactin blood test To use the sharing features on this page, ... test measures the amount of prolactin in the blood. How the Test is Performed A blood sample is needed . How ...

... Gene Mutations Testing Cytomegalovirus (CMV) Tests D-dimer Dengue Fever Testing Des-gamma-carboxy prothrombin (DCP) DHEAS ... caused by a virus and will resolve without treatment within a few days, some people with sore ...

... not well controlled with medicine Hives and angioedema Food allergies Skin rashes ( dermatitis ), in which the skin becomes ... prick test may also be used to diagnose food allergies. Intradermal tests are not used to test for ...

Three small test SDHW systems was tested in a laboratory test facility.The three SDHW systems where all based on the low flow principe and a mantle tank but the design of the systems where different.......Three small test SDHW systems was tested in a laboratory test facility.The three SDHW systems where all based on the low flow principe and a mantle tank but the design of the systems where different....

Thermal-mechanical tests were performed on a titanium honeycomb sandwich panel to experimentally validate the hypersonic wing panel concept and compare test data with analysis. Details of the test article, test fixture development, instrumentation, and test results are presented. After extensive testing to 900 deg. F, non-destructive evaluation of the panel has not detected any significant structural degradation caused by the applied thermal-mechanical loads.

National Aeronautics and Space Administration — Ground vibration tests or modal surveys are routinely conducted to support flutter analysis for subsonic and supersonic vehicles. However, vibration testing...

This research focuses on testing whether or not the hazardous conditions identified by design-level fault tree analysis will occur in the target implementation. Part 1: Integrate fault tree models into functional specifications so as to identify testable interactions between intended behaviors and hazardous conditions. Part 2: Develop a test generator that produces not only functional tests but also safety tests for a target implementation in a cost-effective way. Part 3: Develop a testing environment for executing generated functional and safety tests and evaluating test results against expected behaviors or hazardous conditions. It includes a test harness as well as an environment simulation of external events and conditions.

The desire and ability to fly Unmanned Aircraft Systems (UAS) in the National Airspace System (NAS) is of increasing urgency. The application of unmanned aircraft to perform national security, defense, scientific, and emergency management are driving the critical need for less restrictive access by UAS to the NAS. UAS represent a new capability that will provide a variety of services in the government (public) and commercial (civil) aviation sectors. The growth of this potential industry has not yet been realized due to the lack of a common understanding of what is required to safely operate UAS in the NAS. NASA's UAS Integration into the NAS Project is conducting research in the areas of Separation Assurance/Sense and Avoid Interoperability, Human Systems Integration (HSI), and Communication to support reducing the barriers of UAS access to the NAS. This research is broken into two research themes namely, UAS Integration and Test Infrastructure. UAS Integration focuses on airspace integration procedures and performance standards to enable UAS integration in the air transportation system, covering Sense and Avoid (SAA) performance standards, command and control performance standards, and human systems integration. The focus of Test Infrastructure is to enable development and validation of airspace integration procedures and performance standards, including the integrated test and evaluation. In support of the integrated test and evaluation efforts, the Project will develop an adaptable, scalable, and schedulable relevant test environment capable of evaluating concepts and technologies for unmanned aircraft systems to safely operate in the NAS. To accomplish this task, the Project will conduct a series of Human-in-the-Loop and Flight Test activities that integrate key concepts, technologies and/or procedures in a relevant air traffic environment. Each of the integrated events will build on the technical achievements, fidelity and complexity of the previous tests and

The objective of the Digface Characterization (DFC) Remote Testing project is to remotely deploy a sensor head (Mini-Lab) across a digface to determine if it can characterize the contents below the surface. The purpose of this project is to provide a robotics technology that allows removal of workers from hazards, increases speed of operations, and reduces life cycle costs compared to alternate methods and technologies. The Buried Waste Integrated Demonstration (BWID) is funding the demonstration, testing, and evaluation of DFC. This document describes the test plan for the DFC remote deployment demonstration for the BWID. The purposes of the test plan are to establish test parameters so that the demonstration results are deemed useful and usable and perform the demonstration in a safe manner and within all regulatory requirements

This document is a flight test report from the Operational perspective for Flight Test Series 3, a subpart of the Unmanned Aircraft System (UAS) Integration in the National Airspace System (NAS) project. Flight Test Series 3 testing began on June 15, 2015, and concluded on August 12, 2015. Participants included NASA Ames Research Center, NASA Armstrong Flight Research Center, NASA Glenn Research Center, NASA Langley Research center, General Atomics Aeronautical Systems, Inc., and Honeywell. Key stakeholders analyzed their System Under Test (SUT) in two distinct configurations. Configuration 1, known as Pairwise Encounters, was subdivided into two parts: 1a, involving a low-speed UAS ownship and intruder(s), and 1b, involving a high-speed surrogate ownship and intruder. Configuration 2, known as Full Mission, involved a surrogate ownship, live intruder(s), and integrated virtual traffic. Table 1 is a summary of flights for each configuration, with data collection flights highlighted in green. Section 2 and 3 of this report give an in-depth description of the flight test period, aircraft involved, flight crew, and mission team. Overall, Flight Test 3 gathered excellent data for each SUT. We attribute this successful outcome in large part from the experience that was acquired from the ACAS Xu SS flight test flown in December 2014. Configuration 1 was a tremendous success, thanks to the training, member participation, integration/testing, and in-depth analysis of the flight points. Although Configuration 2 flights were cancelled after 3 data collection flights due to various problems, the lessons learned from this will help the UAS in the NAS project move forward successfully in future flight phases.

This true-false diagnostic test was used for pretesting of employees at a Veterans Administration Hospital. The test is comprised of 20 items. An alternate test--Classification Questionnaire--was used for testing after remedial training. (For related document, see TM 002 334.) (DB)

The breath alcohol test measures the amount of alcohol in the blood by testing exhaled air. The test is performed by blowing ... breath machine 15 minutes after alcohol consumption. The test determines how much alcohol it takes to raise the blood-alcohol level ...

textabstractTwo key aspects of extreme programming (XP) are unit testing and merciless refactoring. Given the fact that the ideal test code / production code ratio approaches 1:1, it is not surprising that unit tests are being refactored. We found that refactoring test code is different from

The Lyme disease blood test looks for antibodies in the blood to the bacteria that causes Lyme disease. The test is used to help ... specialist looks for Lyme disease antibodies in the blood sample using the ELISA test . If the ELISA test is positive, it must ...

ITER has been designed to operate in two phases. The first phase which lasts for 6 years, is devoted to machine checkout and physics testing. The second phase lasts for 8 years and is devoted primarily to technology testing. This report describes the technology test program development for ITER, the ancillary equipment outside the torus necessary to support the test modules, the international collaboration aspects of conducting the test program on ITER, the requirements on the machine major parameters and the R and D program required to develop the test modules for testing in ITER. 15 refs, figs and tabs

The easy way to get practice and excel at numeracy tests Whether you're looking for a new job, applying to certain university courses, or attempting to join the military, you're increasingly likely to face a numeracy test as part of the screening process. And the only way to prepare for a numeracy test is practise. Numeracy Tests For Dummies is an accessible one-stop guide to pass these test. Featuring expert advice, instruction, review, and plenty of practise, Numeracy Tests For Dummies will help you succeed. Numeracy Tests For Dummies contains instruction and revision on:Basic mathematical k

This software runs a suite of arbitrary software tests spanning various software languages and types of tests (unit level, system level, or file comparison tests). The dtest utility can be set to automate periodic testing of large suites of software, as well as running individual tests. It supports distributing multiple tests over multiple CPU cores, if available. The dtest tool is a utility program (written in Python) that scans through a directory (and its subdirectories) and finds all directories that match a certain pattern and then executes any tests in that directory as described in simple configuration files.

The testing stages in NET for the performance assessment of the various breeding blanket concepts developed at the present time in Europe for DEMO (LiPb and ceramic blankets) and the requirements upon NET to perform these tests are reviewed. Typical locations available in NET for blanket testing are the central outboard segments and the horizontal ports of in-vessel sectors. These test positions will be connectable with external test loops. The number of test loops (helium, water, liquid metal) will be such that each major class of blankets can be tested in NET. The test positions, the boundary conditions and the external test loops are identified and the requirements for test blankets are summarized (author). 6

It is important to understand which pancreatic function tests are available and how to interpret them when evaluating patients with malabsorption. Available direct tests are the secretin stimulation test, the Lundh test meal, and measurement of serum or fecal enzymes. Indirect tests assess pancreatic exocrine function by measuring the effect of pancreatic secretion on various nutrients. These include triglycerides labeled with carbon 14, cobalamin labeled with cobalt 57 and cobalt 58, and para-aminobenzoic acid bound to a dipeptide. Of all these tests the secretin stimulation test is the most accurate and reliable if done by experienced personnel. However, the indirect tests are simpler to do and appear to be comparable to the secretin test at detecting pancreatic exocrine insufficiency. These indirect tests are becoming clinically available and clinicians should familiarize themselves with the strengths and weaknesses of each

This thesis deals with the description of software testing in agile projects. Unlike the traditionally managed projects, testing in agile projects is not a discrete phase. In agile managed projects, testing is integrated into the entire development process. Testing takes place continuously throughout the project to ensure frequent delivery of valuable software in short development cycles. The aim of this diploma thesis is to create a comprehensive description of software testing in agile proj...

During the service life, the mechanical properties of the PWR components change. It is necessary to determine precisely this evolution, but it is not always possible to draw a sample with the adequate size for the characterization. For this latter case we intend to calculate the stress-strain curve of a material from a hardness test results, because it is appropriate for testing on site and do not need any particular sample shape. This paper is the first bibliographical part of a larger study on the relation between the values measured during a hardness test (applied load, indentation diameter) and the mechanical properties of a solid obtained by a traction test. We have treated the problem within the general setting of two solids in contact. Thus, we expose general elastic, elasto-plastic and plastic models describing the indentation of a solid by a rigid indenter

This paper defines software fairness and discrimination and develops a testing-based method for measuring if and how much software discriminates, focusing on causality in discriminatory behavior. Evidence of software discrimination has been found in modern software systems that recommend criminal sentences, grant access to financial products, and determine who is allowed to participate in promotions. Our approach, Themis, generates efficient test suites to measure discrimination. Given a sche...

Literature on optical and infrared microvariability in active galactic nuclei (AGNs) reflects a diversity of statistical tests and strategies to detect tiny variations in the light curves of these sources. Comparison between the results obtained using different methodologies is difficult, and the pros and cons of each statistical method are often badly understood or even ignored. Even worse, improperly tested methodologies are becoming more and more common, and biased results may be misleading with regard to the origin of the AGN microvariability. This paper intends to point future research on AGN microvariability toward the use of powerful and well-tested statistical methodologies, providing a reference for choosing the best strategy to obtain unbiased results. Light curves monitoring has been simulated for quasars and for reference and comparison stars. Changes for the quasar light curves include both Gaussian fluctuations and linear variations. Simulated light curves have been analyzed using χ 2 tests, F tests for variances, one-way analyses of variance and C-statistics. Statistical Type I and Type II errors, which indicate the robustness and the power of the tests, have been obtained in each case. One-way analyses of variance and χ 2 prove to be powerful and robust estimators for microvariations, while the C-statistic is not a reliable methodology and its use should be avoided.

This book is focused on the advancements in the field of software testing and the innovative practices that the industry is adopting. Considering the widely varied nature of software testing, the book addresses contemporary aspects that are important for both academia and industry. There are dedicated chapters on seamless high-efficiency frameworks, automation on regression testing, software by search, and system evolution management. There are a host of mathematical models that are promising for software quality improvement by model-based testing. There are three chapters addressing this concern. Students and researchers in particular will find these chapters useful for their mathematical strength and rigor. Other topics covered include uncertainty in testing, software security testing, testing as a service, test technical debt (or test debt), disruption caused by digital advancement (social media, cloud computing, mobile application and data analytics), and challenges and benefits of outsourcing. The book w...

Full Text Available Teaching of a language is a very complicated issue and testing is anindispensable part of this matter. Thanks to testing teachers can assess efficiency ofteaching and learning atmosphere, and can get feedback about their learners. In order torealize this, a test should have some qualifications. One of these qualifications is aboutpragmatics. This paper aims at explaining what makes a test pragmatic and howpragmatic tests can be formed. So, examples of pragmatic tests of different types arepresented with explanations. Their pragmatic components and nature are focused on bygiving example test items on the problematic area of test questions prepared. Finally,the writer states his last words by making further comments and explanations onpragmatics of testing in the conclusion part.

Testing micro optics, i.e. lenses with dimensions down to 0.1mm and less, with high precision requires a dedicated design of the testing device, taking into account propagation and wave-optical effects. In this paper, we discuss testing methods based on Shack-Hartmann wavefront technology for functional testing in transmission and for the measurement of surface shape in reflection. As a first example of more conventional optics testing, i.e. optics in the millimeter range, we present the measurement of binoculars in transmission, and discuss the measured wave aberrations and imaging quality. By repeating the measurement at different wavelengths, information on chromatic effects is retrieved. A task that is often tackled using Shack-Hartman wavefront sensors is the alignment of collimation optics in front of a light source. In case of a micro-optical collimation unit with a 1/e² beam diameter of ca. 1mm, we need adapted relay optics for suitable beam expansion and well-defined imaging conditions. In this example, we will discuss the alignment process and effects of the relay optics magnification, as well as typical performance data. Oftentimes, micro optics are fabricated not as single pieces, but as mass optics, e.g. by lithographic processes. Thus, in order to reduce tooling and alignment time, an automated test procedure is necessary. We present an approach for the automated testing of wafer- or tray-based micro optics, and discuss transmission and reflection measurement capabilities. Exemplary performance data is shown for a sample type with 30 microns in diameter, where typical repeatabilities of a few nanometers (rms) are reached.

The Gas Test Loop (GTL) project is for the design of an adaptation to the Advanced Test Reactor (ATR) to create a fast-flux test space where fuels and materials for advanced reactor concepts can undergo irradiation testing. Incident to that design, it was found necessary to make use of special booster fuel to enhance the neutron flux in the reactor lobe in which the Gas Test Loop will be installed. Because the booster fuel is of a different composition and configuration from standard ATR fuel, it is necessary to qualify the booster fuel for use in the ATR. Part of that qualification is the determination that required thermal hydraulic criteria will be met under routine operation and under selected accident scenarios. The Hydraulic Testing task in the GTL project facilitates that determination by measuring flow coefficients (pressure drops) over various regions of the booster fuel over a range of primary coolant flow rates. A high-fidelity model of the NW lobe of the ATR with associated flow baffle, in-pile-tube, and below-core flow channels was designed, constructed and located in the Idaho State University Thermal Fluids Laboratory. A circulation loop was designed and constructed by the university to provide reactor-relevant water flow rates to the test system. Models of the four booster fuel elements required for GTL operation were fabricated from aluminum (no uranium or means of heating) and placed in the flow channel. One of these was instrumented with Pitot tubes to measure flow velocities in the channels between the three booster fuel plates and between the innermost and outermost plates and the side walls of the flow annulus. Flow coefficients in the range of 4 to 6.5 were determined from the measurements made for the upper and middle parts of the booster fuel elements. The flow coefficient for the lower end of the booster fuel and the sub-core flow channel was lower at 2.3.

This textbook provides a self-contained presentation of the main concepts and methods of nonparametric statistical testing, with a particular focus on the theoretical foundations of goodness-of-fit tests, rank tests, resampling tests, and projection tests. The substitution principle is employed as a unified approach to the nonparametric test problems discussed. In addition to mathematical theory, it also includes numerous examples and computer implementations. The book is intended for advanced undergraduate, graduate, and postdoc students as well as young researchers. Readers should be familiar with the basic concepts of mathematical statistics typically covered in introductory statistics courses.

This document includes a definition of the comparative test cases DSF200_3 and DSF200_4, which previously described in the comparative test case specification for the test cases DSF100_3 and DSF200_3 [Ref.1]....... This document includes a definition of the comparative test cases DSF200_3 and DSF200_4, which previously described in the comparative test case specification for the test cases DSF100_3 and DSF200_3 [Ref.1]....

Testing is a major approach for the detection of software defects, including vulnerabilities in security features. This article introduces metamorphic testing (MT), a relatively new testing method, and discusses how the new perspective of MT can help to conduct negative testing as well as to alleviate the oracle problem in the testing of security-related functionality and behavior. As demonstrated by the effectiveness of MT in detecting previously unknown bugs in real-world critical applications such as compilers and code obfuscators, we conclude that software testing of security-related features should be conducted from diverse perspectives in order to achieve greater cybersecurity.

The report describes the results of a test using four 0.97-m long PWR-type fuel rods with differences in diametral gap and cladding irradiation. The objective of this test was to provide information about the effects of these differences on fuel rod behavior during quasi-equilibrium and film boiling operation. The fuel rods were subjected to a series of preconditioning power cycles of less than 30 kW/m. Rod powers were then increased to 68 kW/m at a coolant mass flux of 4900 kg/s-m 2 . After one hour at 68 kW/m, a power-cooling-mismatch sequence was initiated by a flow reduction at constant power. At a flow of 2550 kg/s-m 2 , the onset of film boiling occurred on one rod, Rod IE-011. An additional flow reduction to 2245 kg/s-m 2 caused the onset of film boiling on the remaining three rods. Data are presented on the behavior of fuel rods during quasiequilibrium and during film boiling operation. The effects of initial gap size, cladding irradiation, rod power cycling, a rapid power increase, and sustained film boiling are discussed. These discussions are based on measured test data, preliminary postirradiation examination results, and comparisons of results with FRAP-T3 computer model calculations

Uric acid urine test is performed to check for the amount of uric acid in urine. Urine is collected over a 24 ... for testing. The most common reason for measuring uric acid levels is in the diagnosis or treatment of ...

... become tired. This is expected. ■■ If you become light-headed or dizzy during this test, immediately stop blowing and let the staff know. What are diffusion studies? Diffusion tests find out how well the ...

... this page: //medlineplus.gov/ency/article/003584.htm Leukocyte esterase urine test To use the sharing features on this page, please enable JavaScript. Leukocyte esterase is a urine test to look for ...

The large-scale reflood test with a view to ensuring the safety of light water reactors was started in fiscal 1976 based on the special account act for power source development promotion measures by the entrustment from the Science and Technology Agency. Thereafter, to establish the safety of PWRs in loss-of-coolant accidents by joint international efforts, the Japan-West Germany-U.S. research cooperation program was started in April, 1980. Thereupon, the large-scale reflood test is now included in this program. It consists of two tests using a cylindrical core testing apparatus for examining the overall system effect and a plate core testing apparatus for testing individual effects. Each apparatus is composed of the mock-ups of pressure vessel, primary loop, containment vessel and ECCS. The testing method, the test results and the research cooperation program are described. (J.P.N.)

... page: //medlineplus.gov/ency/article/003377.htm Growth hormone stimulation test To use the sharing features on this page, please enable JavaScript. The growth hormone (GH) stimulation test measures the ability of the ...

This book is ideal if you want to learn about the testing disciplines and automated testing tools from a hands-on, conversational guide. You should already know Python and be comfortable with Python 3.

... whether the problem is in the pituitary gland ( Cushing disease ). Dexamethasone is a man-made (synthetic) steroid that ... dose test can help tell a pituitary cause (Cushing disease) from other causes. An ACTH blood test may ...

According to the 2005 International Technology Roadmap for Semiconductors, the integration of emerging nondigital CMOS technologies will require radically different test methods, posing a major challenge for designers and test engineers. One such technology is microelectronic fluidic (MEF) arrays,

... medlineplus.gov/ency/article/003403.htm Cord blood testing To use the sharing features on this page, ... the baby to the mother's womb. Cord blood testing can be done to evaluate a newborn's health. ...

In this paper, we present the results of a pilot study in Denmark of cross cultural effects on Think Aloud usability testing. We provide an overview of previous research on cross cultural usability evaluation with a special focus on the relationship between the evaluator and the test user....... This relation was studied in an experiment with usability testing of a localized clipart application in which eight participants from Denmark and India formed pairs of evaluator-test user. The test users were asked to think aloud and the evaluators' role were to facilitate the test users thinking aloud...... and hereby identify usability problems with the clipart application. Data on the evaluators' and test users' behaviour were recorded and analyzed by coding and summarizing statistics on these behavioural events. The results show that Think Aloud Usability Test of a localized application is most effectively...

... medlineplus.gov/ency/article/003854.htm Lung diffusion testing To use the sharing features on this page, please enable JavaScript. Lung diffusion testing measures how well the lungs exchange gases. This ...

... medlineplus.gov/ency/article/003587.htm Urine specific gravity test To use the sharing features on this page, please enable JavaScript. Urine specific gravity is a laboratory test that shows the concentration ...

... page: //medlineplus.gov/ency/article/003608.htm Urine concentration test To use the sharing features on this page, please enable JavaScript. A urine concentration test measures the ability of the kidneys to ...

... this page: //medlineplus.gov/ency/article/003396.htm Visual acuity test To use the sharing features on this page, please enable JavaScript. The visual acuity test is used to determine the smallest ...

If you are an Android developer looking to test your applications or optimize your application development process, then this book is for you. No previous experience in application testing is required.

Full Text Available It is essential to regularly test the usability of a learning management system, in order to ensure a fast adoption by new users and rapidly shift the focus from the platform to the content and the learning experience. Quantitative testing yields the most reliable results due to the large number of data points acquired, but lacks the in-depth analysis of the qualitative research from a controlled testing setup. We are proposing in this paper an integrated usability testing tool, which can replace a certain type of laboratory testing, where the users’ actions on the real platform are measured and analyzed. We conducted tests with the tool and compared the results with a small scale laboratory test using the same scenarios. The results seem to confirm the proposed tool as a viable alternative to the laboratory test.

... from a vein. The test is called a venipuncture . If you are in the hospital, this test ... Guidelines Viewers & Players MedlinePlus Connect for EHRs For Developers U.S. National Library of Medicine 8600 Rockville Pike, ...

A total of 61 cone penetration tests were performed at 14 sites in the state of Wisconsin. Data : reinforced conclusions from practice in Minnesota and previously performed test programs : related to the Marquette Interchange and Mitchell interchange...

The PANDA test facility at PSI in Switzerland is used to study the long-term Simplified Boiling Water Reactor (SBWRT) Passive Containment Cooling System (PCCS) performance. The PANDA tests demonstrate performance on a larger scale than previous tests and examine the effects of any non-uniform spatial distributions of steam and noncondensables in the system. The PANDA facility is in 1:1 vertical scale, and 1:25 'system' scale (volume, power, etc.). Steady-state PCCS condenser performance tests and extensive facility characterization tests have already been conducted. A series of transient system behavior tests have been completed by end of 1995. Results from the first three transient tests (M3 series) are reviewed. The first PANDA tests exhibited reproducibility, and indicated that the SBWR containment is likely to be favorably responsive and highly robust to changes in the thermal transport patterns. (author) 6 figs., 11 refs

... page: //medlineplus.gov/ency/article/003469.htm CO2 blood test To use the sharing features on this page, ... a substance called bicarbonate (HCO3-). Therefore, the CO2 blood test is really a measure of your blood bicarbonate ...

Peptic ulcer - gastrin blood test ... A blood sample is needed . ... in the stomach, gastrin is released into the blood. As the acid ... provider may order this test if you have signs or symptoms of a ...

... page: //medlineplus.gov/ency/article/003509.htm HCG blood test - qualitative To use the sharing features on this page, please enable JavaScript. A qualitative HCG blood test checks if there is a hormone called human ...

... page: https://medlineplus.gov/labtests/mpvbloodtest.html MPV Blood Test To use the sharing features on this page, please enable JavaScript. What is an MPV Blood Test? MPV stands for mean platelet volume. Platelets are ...

... page: //medlineplus.gov/ency/article/003478.htm Phosphorus blood test To use the sharing features on this page, please enable JavaScript. The phosphorus blood test measures the amount of phosphate in the blood. ...

... page: //medlineplus.gov/ency/article/003490.htm Ferritin blood test To use the sharing features on this page, please enable JavaScript. The ferritin blood test measures the level of ferritin in the blood. ...

Carcinoembryonic antigen blood test ... doing so for a short time before the test. ... When the needle is inserted to draw blood, some people feel ... may be some throbbing or a slight bruise. This soon goes away.

... page: //medlineplus.gov/ency/article/003704.htm Aldosterone blood test To use the sharing features on this page, please enable JavaScript. The aldosterone blood test measures the level of the hormone aldosterone in ...

... page: //medlineplus.gov/ency/article/003470.htm ALP - blood test To use the sharing features on this page, ... include the liver, bile ducts, and bone. A blood test can be done to measure the level of ...

... medlineplus.gov/ency/article/003565.htm Methylmalonic acid blood test To use the sharing features on this page, please enable JavaScript. The methylmalonic acid blood test measures the amount of methylmalonic acid in the ...

... page: //medlineplus.gov/ency/article/003374.htm TBG - blood test To use the sharing features on this page, please enable JavaScript. The TBG blood test measures the level of a protein that moves ...

... page: //medlineplus.gov/ency/article/003534.htm Anthrax blood test To use the sharing features on this page, please enable JavaScript. The anthrax blood test is used to measure substances (proteins) called antibodies , ...

... page: //medlineplus.gov/ency/article/003699.htm Calcitonin blood test To use the sharing features on this page, please enable JavaScript. The calcitonin blood test measures the level of the hormone calcitonin in ...

... page: //medlineplus.gov/ency/article/003477.htm Calcium blood test To use the sharing features on this page, please enable JavaScript. The calcium blood test measures the level of calcium in the blood. ...

... page: //medlineplus.gov/ency/article/003716.htm Glucagon blood test To use the sharing features on this page, please enable JavaScript. A glucagon blood test measures the amount of a hormone called glucagon ...

... medlineplus.gov/ency/article/003357.htm Pyruvate kinase blood test To use the sharing features on this page, ... energy when oxygen levels are low. How the Test is Performed A blood sample is needed. In the laboratory, white blood ...

... page: //medlineplus.gov/ency/article/003695.htm ACTH blood test To use the sharing features on this page, ... the adrenal gland . It regulates blood pressure and blood sugar. This test can help find the causes of certain hormone ...

... page: //medlineplus.gov/ency/article/003634.htm Haptoglobin blood test To use the sharing features on this page, please enable JavaScript. The haptoglobin blood test measures the level of haptoglobin in your blood. ...

Antibody Blood Tests Researchers have discovered that people with celiac disease who eat gluten have higher than normal levels of ... do I do if I have a negative blood test (or panel) but I’m still having symptoms? ...

... medlineplus.gov/ency/article/003661.htm Antithrombin III blood test To use the sharing features on this page, ... a protein that helps control blood clotting. A blood test can determine the amount of AT III present ...

... medlineplus.gov/ency/article/003373.htm Fibrinopeptide A blood test To use the sharing features on this page, ... measure the level of this substance in your blood. How the Test is Performed A blood sample is needed. How ...

The PANDA test facility at PSI in Switzerland is used to study the long-term Simplified Boiling Water Reactor (SBWR) Passive Containment Cooling System (PCCS) performance. The PANDA tests demonstrate performance on a larger scale than previous tests and examine the effects of any non-uniform spatial distributions of steam and non-condensables in the system. The PANDA facility has a 1:1 vertical scale, and 1:25 ''system'' scale (volume, power, etc.). Steady-state PCCS condenser performance tests and extensive facility characterization tests have been completed. Transient system behavior tests were conducted late in 1995; results from the first three transient tests (M3 series) are reviewed. The first PANDA tests showed that the overall global behavior of the SBWR containment was globally repeatable and very favorable; the system exhibited great ''robustness.''

In this paper, we design a test apparatus Transistor Specification. Specification is atype of transistor is a transistor and common emitter current reinforcement value ( βDC ). The system will provide information in the form of an LED display emits greenlight when the tested types of NPN transistor and the second LED emits blue lightwhen the tested types of PNP transistors.To test the value of β, whose value is proportional to the display used by the collectorcurrent Ic.

In the framework of mechanical tests and to answer the different requests for tests, the T.C.R (Transport Conditionnement et Retraitement) laboratory got test facilities. These installations allow to carry out tests of resistance to shocks, mainly at the safety level of components of nuclear power plants, mockups of transport casks for fuel elements and transport containers for radioactive materials. They include a tower and a catapult. This paper give a decription of the facilities and explain their operation way [fr

Omnibus tests for central symmetry of a bivariate probability distribution are proposed. The test statistics compare empirical measures of opposite regions. Under rather weak conditions, we establish the asymptotic distribution of the test statistics under the null hypothesis; it follows that they

Because of its exceptional size, it was not feasible to assemble and test the Barrel Toroid - made of eight coils - as an integrated toroid on the surface, prior to its final installation underground in LHC interaction point 1. It was therefore decided to test these eight coils individually in a dedicated test facility.

This book is packed with the step by step tutorial and instructions in recipe format helping you setup test infrastructure and gradually advance your skills to plan, develop, and test your backbone applications.If you are a JavaScript developer looking for recipes to create and implement test support for your backbone application, then this book is ideal for you.

Software testing is presented as a so-called theme within which different authors and groups have defined different subjects each of these subjects having a different focus on testing. A uniform concept of software testing is non-existent and the space of possible coherent perspectives on software

of the disease, and may be nonspecific. A number of recently developed quantifiable and reproducible autonomic nerve function tests are reviewed, with emphasis on the physiological basis of the tests and on practical applicability. Finally, diagnostic criteria, based on autonomic nerve function tests...

Usability testing seems complicated and time-consuming. Is it though? In fact, it is the best way to understand how real users experience your product. In this interactive session, we will do a live usability test and you will get advice on how to conduct your own usability tests.

Probe is developed to test strength of soldered, brazed or microwelded joints. It consists of a spring which may be adjusted to the desired test pressure by means of a threaded probe head, and an indicator lamp. Device may be used for electronic equipment testing.

The actuator technology required for AMSD and subsequently NGST are critical in the successful development for future cryogenic systems. Kodak has undertaken an extensive test plan to determine the performance of the force actuators developed under the AMSD program. These actuators are currently in testing at MSFC and are expected to finish this test cycle in early June 2002.

The Chi square test is a statistical test which measures the association between two categorical variables. A working knowledge of tests of this nature are important for the chiropractor and osteopath in order to be able to critically appraise the literature.

... page: //medlineplus.gov/ency/article/003711.htm Estradiol blood test To use the sharing features on this page, ... of estrogens. How the Test is Performed A blood sample is needed . How to Prepare for the Test Your health care provider may tell you to ...

The creatinine blood test measures the level of creatinine in the blood. This test is done to see how well your kidneys ... There are many other conditions for which the test may be ordered, ... pressure, diabetes, or medicine overdose. Your provider will ...

Explains why in the United States the feeling is increasing that much of the aptitude testing now being done discriminates against minority group members seeking employment. Skeptical of eliminating the discriminatory aspects of testing, the article raises the question of eliminating testing itself. (DM)

Includes one diagnostic test and three complete tests, all questions answered and explained, self-assessment guides, and subject reviews. Also features test strategies, QR codes to short instructional videos, and a detailed appendix with equations, physical constants, and a basic math review.

A number of different schemes for testing superconducting coils in a simulated tokamak environment are analyzed for their merits relative to a set of test criteria. Two of the concepts are examined in more detail: the so-called cluster test scheme, which employs two large background field coils, one on either side of the test coil, and the compact torus, a low-aspect ratio toroidal array of a small number of coils in which all of the coils are essentially test coils. Simulation of the pulsed fields of the tokamak is discussed briefly

This expanded and updated Third Edition of Gopal K. Kanji's best-selling resource on statistical tests covers all the most commonly used tests with information on how to calculate and interpret results with simple datasets. Each entry begins with a short summary statement about the test's purpose, and contains details of the test objective, the limitations (or assumptions) involved, a brief outline of the method, a worked example, and the numerical calculation. 100 Statistical Tests, Third Edition is the one indispensable guide for users of statistical materials and consumers of statistical information at all levels and across all disciplines.

Noninvasive prenatal testing (NIPT) refers to recently developed genetic tests of the maternal serum that allow higher detection rates of trisomy 21 and other chromosomal aneuploidies in high-risk pregnancies. Noninvasive prenatal test analyzes cell-free DNA (cfDNA) in the maternal serum. Approximately 3% to 15% of cfDNA in the maternal blood is of fetal origin. Analysis of cfDNA can help identify fetuses affected with trisomy 21 and several other fetal aneuploidies. Testing can be performed after 9 to 10 weeks' gestation and has a higher sensitivity and specificity for trisomy 21 than other aneuploidy screening test. Noninvasive prenatal test has been studied and validated in singleton pregnancies at risk for trisomy 21 secondary to advanced maternal age, an abnormal serum screen, personal or family history of aneuploidy, or abnormal ultrasound findings, if these are suggestive of trisomy 13, 18, or 21. The utilization of NIPT for genetic screening has increased rapidly since introduction of the first clinical test in October 2011. Currently, there are limitations to NIPT including the possibility of test failure (2.6%-5.4%) and the focus on only the common trisomies. Noninvasive prenatal test is a screening test, and both false-positive (0.2%-1%) and false-negative results can occur. As the technology for NIPT is further evaluated, this test is likely to be increasingly used for prenatal screening. This review provides the obstetric clinician with an update of the current issues concerning NIPT.

INTRODUCTIONThe Regional Earthquake Likelihood Models (RELM) project aims to produce and evaluate alternate models of earthquake potential (probability per unit volume, magnitude, and time) for California. Based on differing assumptions, these models are produced to test the validity of their assumptions and to explore which models should be incorporated in seismic hazard and risk evaluation. Tests based on physical and geological criteria are useful but we focus on statistical methods using future earthquake catalog data only. We envision two evaluations: a test of consistency with observed data and a comparison of all pairs of models for relative consistency. Both tests are based on the likelihood method, and both are fully prospective (i.e., the models are not adjusted to fit the test data). To be tested, each model must assign a probability to any possible event within a specified region of space, time, and magnitude. For our tests the models must use a common format: earthquake rates in specified “bins” with location, magnitude, time, and focal mechanism limits.Seismology cannot yet deterministically predict individual earthquakes; however, it should seek the best possible models for forecasting earthquake occurrence. This paper describes the statistical rules of an experiment to examine and test earthquake forecasts. The primary purposes of the tests described below are to evaluate physical models for earthquakes, assure that source models used in seismic hazard and risk studies are consistent with earthquake data, and provide quantitative measures by which models can be assigned weights in a consensus model or be judged as suitable for particular regions.In this paper we develop a statistical method for testing earthquake likelihood models. A companion paper (Schorlemmer and Gerstenberger 2007, this issue) discusses the actual implementation of these tests in the framework of the RELM initiative.Statistical testing of hypotheses is a common task and a

Full Text Available With absolute normal semen analysis parameters it may not be necessary to shift to specialized tests early but in cases with borderline parameters or with history of fertilization failure in past it becomes necessary to do a battery of tests to evaluate different parameters of spermatozoa. Various sperm function tests are proposed and endorsed by different researchers in addition to the routine evaluation of fertility. These tests detect function of a certain part of spermatozoon and give insight on the events in fertilization of the oocyte. The sperms need to get nutrition from the seminal plasma in the form of fructose and citrate (this can be assessed by fructose qualitative and quantitative estimation, citrate estimation. They should be protected from the bad effects of pus cells and reactive oxygen species (ROS (leukocyte detection test, ROS estimation. Their number should be in sufficient in terms of (count, structure normal to be able to fertilize eggs (semen morphology. Sperms should have intact and functioning membrane to survive harsh environment of vagina and uterine fluids (vitality and hypo-osmotic swelling test, should have good mitochondrial function to be able to provide energy (mitochondrial activity index test. They should also have satisfactory acrosome function to be able to burrow a hole in zona pellucida (acrosome intactness test, zona penetration test. Finally, they should have properly packed DNA in the nucleus to be able to transfer the male genes (nuclear chromatic decondensation test to the oocyte during fertilization.

In this report period, efforts have concentrated on defining the requirements for shallow-flaw beam testing. Analyses have been made to envelope the significant parameters for both deep- and shallow-flaw beams for three-point loading; that is, load to initiation of a frangible flaw, load to plastic collapse, LLD, and CMOD. An assessment was made of facilities capable of performing the tests identified by the parametric analyses discussed above. Two testing machines were identified for performing the scoped test series, the first a 550-kip Instron machine assigned to the Pressure Vessel Technology Section located in Building 9204-1 at the Y-12 Plant and the second a 220-kip MTS machine assigned to a mechanical testing group located at the K-25 Site. An existing bend test fixture previously used in the HSST clad plate test series is being modified for use in testing beams under other sponsorship but will be available for shared usage with the HSST shallow-flaw beam testing activities. To prevent the shared usage from having an adverse impact on the logistics of the HSST Program, the decision was made to procure a bend test fixture tailored specifically to serve the shallow flaw beam test series. A specification was prepared and procurement initiated. A survey is in progress for determining sources and costs of displacement-measuring instrumentation from both foreign and domestic sources. It appears that existing direct current displacement transducers available to the HSST Program may be adequate for the LLD measurements. These devices will be employed in the shakedown tests that are planned. A safety and environmental survey assessment for the beam testing conforming to the revised DOE rules has been prepared and approved

Full Text Available Given the high stakes of teacher testing, there is no doubt that every teacher test should meet the industry guidelines set forth in the Standards for Educational and Psychological Testing. Unfortunately, however, there is no public or private business or governmental agency that serves to certify or in any other formal way declare that any teacher test does, in fact, meet the psychometric recommendations stipulated in the Standards. Consequently, there are no legislated penalties for faulty products (tests nor are there opportunities for test takers simply to raise questions about a test and to have their questions taken seriously by an impartial panel. The purpose of this article is to highlight some of the psychometric results reported by National Evaluation Systems (NES in their 1999 Massachusetts Educator Certification Test (MECT Technical Report, and more specifically, to identify those technical characteristics of the MECT that are inconsistent with the Standards. A second purpose of this article is to call for the establishment of a standing test auditing organization with investigation and sanctioning power. The significance of the present analysis is twofold: a psychometric results for the MECT are similar in nature to psychometric results presented as evidence of test development flaws in an Alabama class-action lawsuit dealing with teacher certification (an NES-designed testing system; and b there was no impartial enforcement agency to whom complaints about the Alabama tests could be brought, other than the court, nor is there any such agency to whom complaints about the Massachusetts tests can be brought. I begin by reviewing NES's role in Allen v. Alabama State Board of Education, 81-697-N. Next I explain the purpose and interpretation of standard item analysis procedures and statistics. Finally, I present results taken directly from the 1999 MECT Technical Report and compare them to procedures, results, and consequences of

The design concept of “Crashworthiness” requires the information on material behaviour under dynamic impact loading in order to describe and predict the crash behaviour of structures. Especially the transport related industries, like car, railway or aircraft industry, pursue the concept of lightweight design for a while now. The materials' maximum constraint during loading is pushed to permanently increasing figures. This means in terms of crashworthiness that the process of energy absorption in structures and the mechanical behaviour of materials must well understood and can be described appropriately by material models. In close cooperation with experts from various industries and research institutes Instron has developed throughout the past years a new family of servohydraulic testing machines specifically designed to cope with the dynamics of high rate testing. Main development steps are reflected versus their experimental necessities.

1.1 This test method defines the procedure for evaluating the corrosivity of aircraft maintenance chemicals, when present between faying surfaces (sandwich) of aluminum alloys commonly used for aircraft structures. This test method is intended to be used in the qualification and approval of compounds employed in aircraft maintenance operations. 1.2 The values stated in SI units are to be regarded as the standard. The values given in parentheses are for information. 1.3 This standard may involve hazardous materials, operations, and equipment. This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety and health practices and determine the applicability of regulatory limitations prior to use. Specific hazard statements appear in Section 9.

In the evaluation of the safety of radioactive material transportation it is important to consider the response of Type B packages to environments more severe than that prescribed by the hypothetical accident sequence in Title 10 Part 71 of the Code of Federal Regulations (NRC 1995). The impact event in this sequence is a 9-meter drop onto an essentially unyielding target, resulting in an impact velocity of 13.4 m/s. The behavior of 9 packages when subjected to impacts more severe than this is not well known. It is the purpose of this program to evaluate the structural response of a test package to these environments. Several types of structural response are considered. Of primary importance is the behavior of the package containment boundary, including the bolted closure and 0-rings. Other areas of concern are loss of shielding capability due to lead slump and the deceleration loading of package contents, that may cause damage to them. This type of information is essential for conducting accurate risk assessments on the transportation of radioactive materials. Currently very conservative estimates of the loss of package protection are used in these assessments. This paper will summarize the results of a regulatory impact test and three extra-regulatory impact tests on a sample package

Limb apraxia comprises many different and common disorders, which are largely unrecognized essentially because there is no easy-to-use screening test sensitive enough to identify all types of limb praxis deficits. We evaluated 70 right-handed patients with limb apraxia due to a single focal lesion of the left hemisphere and 40 normal controls, using a new apraxia screening test. The test covered 12 items including: intransitive gestures, transitive gestures elicited under verbal, visual, and tactile modalities, imitation of meaningful and meaningless postures and movements, and a multiple object test. Interrater reliability was maximum for a cutoff of >2 positive items identifying apraxia on the short battery (Cohen's kappa .918, p 3 items (Cohen's kappa .768, p 2 was higher, indicating greater apraxia diagnosis agreement between raters at this cutoff value. The screening test proved to have high specificity and sensitivity to diagnose every type of upper limb praxis deficit, thus showing advantages over previously published tests.

Routine testing and prophylaxis is considered in terms of haematological disorders, biochemical testing, hormonal testing, screening for gestational diabetes and nutritional deficiencies. Within these headings the place of routine supplementation of pregnant women with iron, vitamins, trace elements and an increased protein/calorie intake is discussed. Screening for haemoglobinopathies, irregular blood group antibodies and gestational diabetes is dealt with in detail. The place for routine prophylaxis with anti-D is considered. Biochemical and hormonal testing is covered with particular reference to the use of biochemical and hormonal assays as placental function tests and their use in assessing fetal well-being. In this respect the use of biochemical and hormonal tests to screen a pregnant population for intrauterine growth retardation is also discussed.

The pilocarpine iontophoresis test (P-test) is used as a predictor of the capacity to produce sweat. Therefore, we studied the reproducibility of this test in 12 normal subjects on 10 consecutive days. Furthermore, we determined whether the P-test reflects whole-body and regional sweat secretion...... during exercise in the heat. Finally, we determined whether the P-test stimulates the eccrine sweat glands to maximal sweat secretion. Six growth hormone-deficient (GHD) patients who are known to have decreased sweating, and 11 healthy control subjects were studied. To induce maximal sweat secretion......, the patients exercised on a bicycle ergometer at a workload corresponding to 40% of their maximal aerobic power (VO2max). The 11 healthy subjects exercised at a workload of 150 W. All subjects exercised for 60 min in ambient air at 35 degrees C, with 50% relative humidity. The P-test showed a mean day...

Fracture mechanics and fatigue calculations for WWER reactor pressure vessels were checked by large scale model testing performed using large testing machine ZZ 8000 (with a maximum load of 80 MN) at the SKODA WORKS. The results are described from testing the material resistance to fracture (non-ductile). The testing included the base materials and welded joints. The rated specimen thickness was 150 mm with defects of a depth between 15 and 100 mm. The results are also presented of nozzles of 850 mm inner diameter in a scale of 1:3; static, cyclic, and dynamic tests were performed without and with surface defects (15, 30 and 45 mm deep). During cyclic tests the crack growth rate in the elastic-plastic region was also determined. (author). 6 figs., 2 tabs., 5 refs

Testing plan should include Safety guide Q4 - Inspection and testing - A testing plan should be prepared including following information: General information (facility name, item or system reference, procurement document reference, document reference number and status, associated procedures and drawings); A sequential listing of all testing activities; Procedure, work instruction, specification or standard to be followed in respect of each operation and test; Acceptance criteria; Identification of who is performing tests; Identification of hold points; Type of records to be prepared for each test; Persons and organizations having authority for final acceptance. Proposed activities sequence is: visual, electrical and mechanical checks; environmental tests (thermal aging, vibrations aging, radioactive aging); performance evaluation in extreme conditions; dynamic tests with functional checks; final electrical and mechanical checks The planning of the tests should always be performed taking into account an interpretative model: a very tight cooperation is advisable between experimental people and numerical people dealing with the analysis of more or less complex models for the seismic assessment of structures and components. Preparatory phase should include the choice of the following items should be agreed upon with the final user of the tests: Excitation points, Excitation types, Excitation amplitude with respect to frequency, Measuring points. Data acquisition, recording and storage, should take into account the characteristics of the successive data processing: to much data can be cumbersome to be processed, but to few data can make unusable the experimental results. The parameters for time history acquisition should be chosen taking into account data processing: for Shock Response Spectrum calculation some special requirements should be met: frequency bounded signal, high frequency sampling, shock noise. For stationary random-like excitation, the sample length

Nondestructive testing (NDT) is the use of physical and chemical methods for evaluating material integrity without impairing its intended usefulness or continuing service. Nondestructive tests are used by manufaturer's for the following reasons: 1) to ensure product reliability; 2) to prevent accidents and save human lives; 3) to aid in better product design; 4) to control manufacturing processes; and 5) to maintain a uniform quality level. Nondestructive testing is used extensively on power plants, oil and chemical refineries, offshore oil rigs and pipeline (NDT can even be conducted underwater), welds on tanks, boilers, pressure vessels and heat exchengers. NDT is now being used for testing concrete and composite materials. Because of the criticality of its application, NDT should be performed and the results evaluated by qualified personnel. There are five basic nondestructive examination methods: 1) liquid penetrant testing - method used for detecting surface flaws in materials. This method can be used for metallic and nonmetallic materials, portable and relatively inexpensive. 2) magnetic particle testing - method used to detect surface and subsurface flaws in ferromagnetic materials; 3) radiographic testing - method used to detect internal flaws and significant variation in material composition and thickness; 4) ultrasonic testing - method used to detect internal and external flaws in materials. This method uses ultrasonics to measure thickness of a material or to examine the internal structure for discontinuities. 5) eddy current testing - method used to detect surface and subsurface flaws in conductive materials. Not one nondestructive examination method can find all discontinuities in all of the materials capable of being tested. The most important consideration is for the specifier of the test to be familiar with the test method and its applicability to the type and geometry of the material and the flaws to be detected

The purpose of this Performance Testing Program Plan is to identify the process and phased approach that will be implemented at Site XYZ . The purpose of the testing program at Site XYZ is specifically designed to evaluate the effectiveness of systems that are employed at this site. This plan defines tasks to be accomplished to ensure that performance testing is conducted as effectively and efficiently as possible.

The goal of the GTF (Geothermal Test Facility) Test Program is to evaluate the geothermal resources in the Niland area and determine if they can be effectively converted into electric power. This program will examine the four critical areas of geothermal power development: (I) reservoir analysis, (II) energy extraction and conversion, (III) environmental effects, and (IV) operation and maintenance. These areas are discussed and a detailed test program is presented.

General procedures for software verification and validation are provided as a guide for managers, programmers, and analysts involved in software development. The verification and validation procedures described are based primarily on testing techniques. Testing refers to the execution of all or part of a software system for the purpose of detecting errors. Planning, execution, and analysis of tests are outlined in this document. Code reading and static analysis techniques for software verification are also described.

The NBT test is a non-specific test of neutrophil membrane stimulation which has application to the study of neutrophil function, particularly in the septicaemic patient. An improved cytochemical test which eliminates potential sources of laboratory error has been developed. Venous or capillary blood samples may be studied and the technique can be applied to the neutropenic patient since available neutrophils are concentrated by cytocentrifugation. Clinical evaluation in 443 patients is described. PMID:1184763

A hollow fitting for use in gas spectrometry leak testing of conduit joints is divided into two generally symmetrical halves along the axis of the conduit. A clip may quickly and easily fasten and unfasten the halves around the conduit joint under test. Each end of the fitting is sealable with a yieldable material, such as a piece of foam rubber. An orifice is provided in a wall of the fitting for the insertion or detection of helium during testing. One half of the fitting also may be employed to test joints mounted against a surface.

As part of the Nuclear Systems Office Fission Surface Power Technology Demonstration Unit (TDU) project, a reactor simulator test loop (RxSim) was design & built to perform integrated testing of the TDU components. In particular, the objectives of RxSim testing was to verify the operation of the core simulator, the instrumentation and control system, and the ground support gas and vacuum test equipment. In addition, it was decided to include a thermal test of a cold trap purification design and a pump performance test at pump voltages up to 150 V since the targeted mass flow rate of 1.75 kg/s was not obtained in the RxSim at the originally constrained voltage of 120 V. This paper summarizes RxSim testing. The gas and vacuum ground support test equipment performed effectively in NaK fill, loop pressurization, and NaK drain operations. The instrumentation and control system effectively controlled loop temperature and flow rates or pump voltage to targeted settings. The cold trap design was able to obtain the targeted cold temperature of 480 K. An outlet temperature of 636 K was obtained which was lower than the predicted 750 K but 156 K higher than the cold temperature indicating the design provided some heat regeneration. The annular linear induction pump (ALIP) tested was able to produce a maximum flow rate of 1.53 kg/s at 800 K when operated at 150 V and 53 Hz.

With over 100 models of unmanned vehicles now available for military and civilian safety, security or rescue applications, it is important to for agencies to establish acceptance testing. However, there appears to be no general guidelines for what constitutes a reasonable acceptance test. This paper describes i) a preliminary method for acceptance testing by a customer of the mechanical and electrical components of an unmanned ground vehicle system, ii) how it has been applied to a man-packable micro-robot, and iii) discusses the value of testing both to ensure that the customer has a workable system and to improve design. The test method automated the operation of the robot to repeatedly exercise all aspects and combinations of components on the robot for 6 hours. The acceptance testing process uncovered many failures consistent with those shown to occur in the field, showing that testing by the user does predict failures. The process also demonstrated that the testing by the manufacturer can provide important design data that can be used to identify, diagnose, and prevent long-term problems. Also, the structured testing environment showed that sensor systems can be used to predict errors and changes in performance, as well as uncovering unmodeled behavior in subsystems.

This paper describes the results from aging, condition monitoring, and loss-of-coolant accident (LOCA) testing of class 1E electrical cables, per NUREG/CR-5772. This test was designed to test the performance of cables which had been aged with simultaneous radiation and thermal exposure. The tested cables included crosslinked polyolefin cables, ethylene propylene rubber cables, and miscellaneous cable types. Cables were exposed to 20, 40, and 60 years equivalent aging, and then exposed to LOCA tests at the end of their qualified life to determine the minimum insulation thickness needed for survival of the test. Failures were found in a large number of the tested cables. As a result the NRC has sent information notices to the industry regarding potential insulation problems. The results have raised the question of whether the artificial aging methods provide adequate testing methods. As a result of this testing the NRC is reviewing the artificial aging procedures, the adequacy of environmental qualification requirements for cable safety, and reexamining data from condition monitoring of installed cables

Final design of the facility is nearing completion, and 20% of the construction has been accomplished. A large vacuum chamber, houses the test assembly which is coupled to appropriate cryogenic, electrical, instrumentation, diagnostc systems. Adequate assembly/disassembly areas, shop space, test control center, offices, and test support laboratories are located in the same building. Assembly and installation operations are accomplished with an overhead crane. The major subsystems are the vacuum system, the test stand assembly, the cryogenic system, the experimental electric power system, the instrumentation and control system, and the data aquisition system

An apparatus for compressive testing of a test specimen may comprise vertically spaced upper and lower platen members between which a test specimen may be placed. The platen members are supported by a fixed support assembly. A load indicator is interposed between the upper platen member and the support assembly for supporting the total weight of the upper platen member and any additional weight which may be placed on it. Operating means are provided for moving the lower platen member upwardly toward the upper platen member whereby an increasing portion of the total weight is transferred from the load indicator to the test specimen.

Designed for students and professionals looking to advance their careers, our test prep gives you everything you need to succeed. Focused chapter reviews cover all the information tested on the GRE Physics exam. Each review chapter contains examples to reinforce key concepts. The book includes four full-length practice tests based on the most recent GRE Physics exam. Each test contains every type of question that can be expected on the GRE so you can “practice for real” and boost your confidence before taking the exam.

Funds were authorized by the Nuclear Regulatory Commission to provide data needed for confirmation of the suitability of current design standards and regulatory guides for fire protection and control in water reactor power plants. The activities of this program through August 1978 are summarized. A survey of industry to determine current design practices and a screening test to select two cable constructions which were used in small scale and full scale testing are described. Both small and full scale tests to assess the adequacy of fire retardant coatings and full scale tests on fire shields to determine their effectiveness are outlined

Full Text Available Numerical simulations of rockfall trajectories are a standard procedure for evaluating rockfall hazards. For these simulations, corresponding software codes must be calibrated and evaluated based on field data. This study addresses methods of repeatable rockfall tests, and investigates whether it is possible to produce traceable and statistically analysable data. A testing series is described extensively covering how to conduct rockfall experiments and how certain elements of rockfall trajectories can be measured. The tests use acceleration and rotation sensors inside test blocks, a system to determine block positions over time, surveying measurements, and video recordings. All systems are evaluated regarding their usability in the field and for analyses. The highly detailed description of testing methods is the basis for sound understanding and reproducibility of the tests. This article serves as a reference for future publications and other rockfall field tests, both as a guide and as a basis for comparisons. First analyses deliver information on runout with a shadow angle ranging between 21 and 45 degrees for a slope consisting of homogeneous soft soil. A digital elevation model of the test site as well as point clouds of the used test blocks are part of this publication.

This text covers, the underlying principles and some major applications of non-destructive inspection methods. Complete chapters are devoted to each of the following: liquid penetration inspection, magnetic particle inspection, electrical testing, ultrasonic testing and radiography. The concluding chapter introduces the reader to some of the more recent developments in non-destructive inspection.

A new user facility for accelerator R&D, the CERN Linear Electron Accelerator for Research (CLEAR), started operation in August 2017. CLEAR evolved from the former CLIC Test Facility 3 (CTF3) used by the Compact Linear Collider (CLIC). The new facility is able to host and test a broad range of ideas in the accelerator field.

In 2002, the United States Supreme Court confirmed that in the school's role of in loco parentis, drug testing of students who were involved in athletics and extracurricular activities was constitutional. In a state of the union address, George W. Bush stated that drug testing in schools had been effective and was part of "our aggressive…

Positive maximum stress tests in the management of coronary patients are discussed. It is believed that coronary angiography would be the ultimate test to predict the future of patients with coronary heart disease. Progression of angina, myocardial infarction, and death due to heart disease were analyzed.

In this paper, we present the results of a pilot study in Denmark of cross cultural effects on Think Aloud usability testing. We provide an overview of previous research on cross cultural usability evaluation with a special focus on the relationship between the evaluator and the test user...

A brief description of the East Mesa test site is given. The test facility is supplied by brines from three of the existing production wells, each brine having distinctive physical characteristics. Some of the experimental programs involving heat exchangers and power cycles are briefly discussed. These include binary fluid cycles, two-phase expansion cycles, and combination cycles. (MOW)

The Chemical Reactivity Test (CRT) is used to determine the thermal stability of High Explosives (HEs) and chemical compatibility between (HEs) and alien materials. The CRT is one of the small-scale safety tests performed on HE at the High Explosives Applications Facility (HEAF).

Full Text Available Currently, software engineers are increasingly turning to the option of automating functional tests, but not always have successful in this endeavor. Reasons range from low planning until over cost in the process. Some principles that can guide teams in automating these tests are described in this article.

... For Parents / Blood Test: Testosterone What's in this article? What It Is Why It's Done Preparation The Procedure What to Expect Getting the Results Risks Helping Your Child If You Have Questions Print en español Análisis de sangre: testosterona What It Is A testosterone test measures ...

... For Parents / Blood Test: Estradiol What's in this article? What It Is Why It's Done Preparation The Procedure What to Expect Getting the Results Risks Helping Your Child If You Have Questions Print en español Análisis de sangre: estradiol What It Is An estradiol test measures ...

Existing statistical tests for the fit of the Rasch model have been criticized, because they are only sensitive to specific violations of its assumptions. Contingency table methods using loglinear models have been used to test various psychometric models. In this paper, the assumptions of the Rasch

A planter test stand was developed to evaluate individual row-crop metering units in early 2013. This test stand provided the ability to quantify actual seed metering in terms of population, seed spacing, skips, and multiples over a range of meter RPMs and vacuum pressures. Preliminary data has been...

In this thesis we provide a unit testing approach for multi-purposes object-oriented programming languages in the style of Java and C#. Our approach includes the definition of a test specification language which results from extending the programming language with new designated specification

... black stools, or bloody vomit or vomit that looks like coffee grounds. H. pylori testing may also be ordered when a person has completed a regimen of prescribed antibiotics to confirm that the H. pylori bacteria have been eliminated. A follow-up test is ...

[1] This invention relates to over-the-air testing of a device in an anechoic chamber. In particular, the invention is suitable for simulating both uplink and downlink over-the-air communication with a device under test even when the anechoic chamber has different numbers of uplink and downlink...

The Newell Test as it is proposed by Anderson & Lebiere (A&L) has the disadvantage of being too positivistic, stressing areas a theory should cover, instead of attempting to exclude false predictions. Nevertheless, Newell's list can be used as the basis for a more stringent test with a stress on the

... in the body that prevents blood clotting. A blood test can be done to see how much of ... Certain medicines can change blood test results. Tell your health care provider about all the medicines you take. Your provider will tell you if you need ...

Rh factor blood test Overview Rhesus (Rh) factor is an inherited protein found on the surface of red blood cells. If your ... Rh negative, you might need to have another blood test — an antibody screen — during your first trimester and ...

... in your body that prevents blood clotting. A blood test can be done to see how much of ... Certain medicines can change blood test results: Tell your health care provider about all the medicines you take. Your provider will tell you if you need ...

testing will commence after boat alterations and fuel tank cleaning have been accomplished. The Gantt chart in Figure 1 details the proposed testing...transmission intervals; some can be controlled while others cannot. The data collection software will be configured to record all data at the

In this article, the author challenges the implicit assumptions of tests as a neutral tool for measuring the individual’s learning achievement. Instead, testing is explored as a social practice which becomes part of children’s conduct of everyday life. The theoretical foundation for the analysis...... class at a low socio-economic school in Denmark....

The primary method of placement at Portland CC (PCC) is the Compass Placement test. For the most part, students are placed correctly, but there are cases when students feel that they have been placed too low. In such cases we use our newly created Placement Advisory Test (PAT) to help us place them appropriately. (Contains 2 figures.)

Discusses different emphases placed by institutions of higher education on a range of admissions criteria including academic performance, evidence of graduation, letters of recommendation, personal essays, and interviews. Concludes that standardized tests are not the pervasive barrier to higher education in the United States that many test critics…

Ovarian cancer - CA-125 test ... CA-125 is a protein that is found more in ovarian cancer cells than in other cells. This ... ovarian cancer . The test is useful if the CA-125 level was high when the cancer was first ...

... second should occur after 1 year on the gluten-free diet. After that, a celiac should receive follow-up ... test result is straightforward—a celiac on the gluten-free diet should have a negative test. The numerical value ...

region, forming a pink band. This control band. 1 serves to validate the test performance . The appropriateness of microscopy versus antigen- detecting rapid diagnostic tests depends on a number of factors including parasite prevalence, availability of skilled personnel and resources, and the capacity for maintaining quality ...

The purpose of the Thermal Testing Measurements Report (Scientific Analysis Report) is to document, in one report, the comprehensive set of measurements taken within the Yucca Mountain Project Thermal Testing Program since its inception in 1996. Currently, the testing performed and measurements collected are either scattered in many level 3 and level 4 milestone reports or, in the case of the ongoing Drift Scale Test, mostly documented in eight informal progress reports. Documentation in existing reports is uneven in level of detail and quality. Furthermore, while all the data collected within the Yucca Mountain Site Characterization Project (YMP) Thermal Testing Program have been submitted periodically to the Technical Data Management System (TDMS), the data structure--several incremental submittals, and documentation formats--are such that the data are often not user-friendly except to those who acquired and processed the data. The documentation in this report is intended to make data collected within the YMP Thermal Testing Program readily usable to end users, such as those representing the Performance Assessment Project, Repository Design Project, and Engineered Systems Sub-Project. Since either detailed level 3 and level 4 reports exist or the measurements are straightforward, only brief discussions are provided for each data set. These brief discussions for different data sets are intended to impart a clear sense of applicability of data, so that they will be used properly within the context of measurement uncertainty. This approach also keeps this report to a manageable size, an important consideration because the report encompasses nearly all measurements for three long-term thermal tests. As appropriate, thermal testing data currently residing in the TDMS have been reorganized and reformatted from cumbersome, user-unfriendly Input-Data Tracking Numbers (DTNs) into a new set of Output-DTNs. These Output-DTNs provide a readily usable data structure

The synchronization of the LHC's clockwise beam transfer system and the rest of CERN's accelerator chain was successfully achieved last weekend. Tests began on Friday 8 August when a single bunch of a few particles was taken down the transfer line from the SPS accelerator to the LHC. After a period of optimization, one bunch was kicked up from the transfer line into the LHC beam pipe and steered about 3 kilometres around the LHC itself on the first attempt. On Saturday, the test was repeated several times to optimize the transfer before the operations group handed the machine back for hardware commissioning to resume on Sunday. The anti-clockwise synchronization systems will be tested over the weekend of 22 August.Picture:http://lhc-injection-test.web.cern.ch/lhc-injection-test/

Routine patch testing with a series of 6 industrial biocides containing methylene-bis-thiocyanate (Cytox 3522), benzisothiazolin-3-one (BIT), chlorocresol (Preventol CMK), 2-n-octyl-4-isothiazolin-3-one (Kathon 893), polyhydroxymethylene monobenzylether (Preventol D2) or 1,3,5-tris (hydroxy......-ethyl) hexahydrotriazine (Grotan BK) was carried out in 6 Danish out-patient clinics to evaluate guinea pig allergy test results with the same compounds. A total of 1652 consecutive patients with dermatitis were tested. The usefulness of this patch test battery was limited. There were a few positive reactions to Cytox...... of male patients and atopics, but significant differences in the frequencies of occupational cases, hand eczemas, and leg ulcers/stasis dermatitis, indicating possible variations in referral patterns, use of patch tests, and/or environmental factors....

A test was performed to determine whether transporting and handling the undulators makes any changes to their properties. This note documents the test. No significant changes to the test undulator were observed. After the LCLS undulators are tuned and fiducialized in the Magnetic Measurement Facility (MMF), they must be transported to storage buildings and transported to the tunnel. It has been established that the undulators are sensitive to temperature. We wish to know whether the undulators are also sensitive to the vibrations and shocks of transportation. To study this issue, we performed a test in which an undulator was measured in the MMF, transported to the tunnel, brought back to the MMF, and re-measured. This note documents the test and the results.

Cracking of multilayer ceramic capacitors, MLCCs, remains a serious problem for space systems. This problem increases substantially for large size capacitors and in cases when manual soldering is involved or the system experiences mechanical shock or vibration. In any case, a fracture occurs when the sum of external and internal mechanical stresses exceeds the strength of the part. To reduce the probability of cracking, the level of stress should be reduced, e.g. by optimizing the assembly workmanship and rules for board design, and the strength of the parts increased by selecting the most mechanically robust capacitors. The latter might possibly be achieved by selecting MLCCs based on the in-situ measurements of mechanical characteristics using four types of tests: flexural strength, hardness, fracture toughness, and flex bend testing. Note that military specifications MIL-PRF-123 and MIL-PRF-55681 do not have requirements for mechanical testing of the parts. However, specifications for automotive industry components employ two types of mechanical tests: beam load (break strength) test per AEC-Q200-003 and board flex test per AEC-Q200-005. A recent military specification for thin dielectric capacitors, MIL-PRF-32535, has one mechanical test, board flex testing, that is similar to AEC-Q200-005. The purpose of this report was assessment of the efficiency of different mechanical tests for selection robust capacitors and comparison of mechanical characteristics of Base Metal Electrode (BME) and Precious Metal Electrode (PME) capacitors. The report has three parts related to the first three mechanical tests mentioned above.

With the replacement of the current upper-stage ESC-A of the Ariane 5 launcher by an enhanced cryogenic upper-stage, ESA's Ariane 5 Midterm Evolution (A5-ME) program aims to raise the launcher's payload capacity in geostationary transfer orbit from 10 to 12 tons, an increase of 20 %. Increasing the in-orbit delivery capability of the A5-ME launcher requires a versatile, high-performance, evolved cryogenic upper-stage engine suitable for delivering multiple payloads to all kinds of orbits, ranging from low earth orbit to geostationary transfer orbit with increased perigee. In order to meet these requirements the re-ignitable liquid oxygen/liquid hydrogen expander cycle engine VINCI® currently under development is designated to power the future upper stage, featuring a design performance of 180 kN of thrust and 464 s of specific impulse. Since 2010 development tests for the VINCI® engine have been conducted at the test benches P3.2 and P4.1 at DLR test site in Lampoldshausen under the ESA A5-ME program. For the VINCI® combustion chamber development the P3.2 test facility is used, which is the only European thrust chamber test facility. Originally erected for the development of the thrust chamber of the Vulcain engine, in 2003 the test facility was modified that today it is able to simulate vacuum conditions for the ignition and startup of the VINCI® combustion chamber. To maintain the test operations under vacuum conditions over an entire mission life of the VINCI® engine, including re-ignition following long and short coasting phases, between 2000 and 2005 the test facility P4.1 was completely rebuilt into a new high-altitude simulation facility. During the past two P4.1 test campaigns in 2010 and 2011 a series of important milestones were reached in the development of the VINCI® engine. In preparation for future activities within the frame of ESA's A5-ME program DLR has already started the engineering of a stage test facility for the prospective upper stage

A series of tests were conducted to evaluate data transfer rates using the MXIbus architecture. The tests were conducted by the DAQ group in the Physics Research Division. The MXIbus from National Instruments provides a multisystem extension interface bus. It allows multiple VME chassis to be networked. Other bus architectures that can participate in the network include VXIbus, IBM PC-AT bus, Sun Sbus, Mac NuBus and stand-alone instruments with the appropriate MXIbus adapter cards. From a functional standpoint the MXIbus provides the capability to enlarge the address space in a fashion that is transparent to the software application. The tests were designed to measure data throughput when using the MSIbus with other industry off-the-shelf hardware. This report contains discussions on: MXIbus architecture and general guidelines; the commercial hardware and software used in each set of tests; and a brief description of each set of tests, observations and guidelines; the commercial hardware and software used in each set of tests; and a brief description of each set of tests, observations and conclusions

Today the nondestructive testing of materials with transverse weldings would be often neglect. Because the production of this parts will get more expensive it is interesting to test the parts eg. cans with ultrasound. Within this research program we developed a testing device for automatically testing of materials with transverse weldings, e.g. tubes. Functional characteristics: after putting in the test tube in the testing device the transducer is adjusted automatically to the best adjustment. This takes place with three step motors. The mechanic of adjustments gets its information from an optimal computer. The optimal computer processes the signals, which it gets from the automatic evaluator during the adjustment and stores the optimal adjustment parameters. With an additional equipment on can identify the exact source of error, if the testing device turns out and the repairing of the part can take place very fast. With an appropiate mechanical science the devide is useable in a production line with high flow rate. (orig.) [de

Full Text Available Since 2014, there have been admission tests in mathematics for applicants to the Estonian University of Life Sciences for Geodesy, Land Management and Real Estate Planning; Civil Engineering; Hydraulic Engineering and Water Pollution Control; Engineering and Technetronics curricula. According to admission criteria, the test must be taken by students who have not passed the specific mathematics course state exam or when the score was less than 20 points. The admission test may also be taken by those who wish to improve their state exam score. In 2016, there were 126 such applicants of whom 63 took the test. In 2015, the numbers were 129 and 89 and in 2014 150 and 47 accordingly. The test was scored on scale of 100. The arithmetic average of the score was 30.6 points in 2016, 29.03 in 2015 and 18.84 in 2014. The test was considered to be passed with 1 point in 2014 and 20 points in 2015 and 2016. We analyzed test results and gave examples of problems which were solved exceptionally well or not at all.

Hundreds of substances are used daily that can damage eyesight. People's eyes are open to accidental or intentional exposure during the production, transportation, use, and disposal of chemical preparations. Ensuring the safety of consumer products was born during the mid twentieth century in the aftermath of chemical warfare research, and was motivated by the hazards of unsafe cosmetics. Justified by an exigency for public protection, the Draize eye test became a governmentally endorsed method to evaluate the safety of materials meant for use in or around the eyes. The test involves a standardized protocol for instilling agents onto the cornea and conjunctiva of laboratory animals. A sum of ordinal-scale items of the outer eye gives an index of ocular morbidity. Advances in ocular toxicology are challenging the validity, precision, relevance, and need of the Draize eye test. Preclinical product-safety tests with rabbits and other mammals also raise ethical concerns of animal wellbeing. Some use the Draize test as a rallying point for how animals are treated in science and industry. A battery of cellular systems and computer models aim to reduce and ultimately to replace whole-animal testing. Molecular measures of ocular toxicity may eventually allow comprehensive screening in humans. The Draize eye test was created and refined for humanitarian reasons and has assuredly prevented harm. Its destiny is to be progressively supplanted as in vitro and clinical alternatives emerge for assessing irritancy of the ocular surface.

Full Text Available Background and Aim: All activities of daily living need to balance control in static and dynamic movements. In recent years, a numerous increase can be seen in the functional balance assessment tools. Functional balance tests emphasize on static and dynamic balance, balance in weight transfer, the equilibrium response to the imbalances, and functional mobility. These standardized and available tests assess performance and require minimal or no equipment and short time to run. Functional balance is prerequisite for the most static and dynamic activities in daily life and needs sufficient interaction between sensory and motor systems. According to the critical role of balance in everyday life, and wide application of functional balance tests in the diagnosis and assessment of patients, a review of the functional balance tests was performed.Methods: The Google Scholar, PubMed, Science Direct, Scopus, Magiran, Iran Medex, and IranDoc databases were reviewed and the reliable and valid tests which were mostly used by Iranian researchers were assessed.Conclusion: It seems that Berg balance scale (BBS have been studied by Iranian and foreign researches more than the other tests. This test has high reliability and validity in elderly and in the most neurological disorders.

The skin prick test (SPT) is the most common test for the diagnosis of allergy. SPT is performed by pricking the skin, usually in the volar surface of the forearm, with a lancet through a drop of an allergen extract and is usually the first choice test in the diagnostic workup for allergic diseases because of its reliability, safety, convenience and low cost. SPT is minimally invasive and has the advantage of testing multiple allergens in 15 to 20 min. In children, SPT is far less disturbing than venipuncture and is used to obtain a sample of serum to measure specific IgE through in vitro tests. There is a good correlation (about 85-95%) between SPT and in vitro tests. Globally, SPT is an excellent diagnostic tool, with a positive predictive value ranging from 95-100%. SPTs can identify sensitivity to inhalants, foods, some drugs, occupational allergens, hymenoptera venom and latex. However, the relevance of such sensitivity to allergens should always be carefully interpreted in the light of the clinical history, because sensitization and clinical allergy may not coincide. In regards to safety, though the reports of systemic reactions, and particularly anaphylaxis, are very rare, in vitro IgE tests should be preferred if previous severe reactions emerge from the patients clinical history.

Full Text Available Following the world conference on sustainable developmentof ecology, the care for the environment has to be strictlycomplied with, and this should be the task both of every individualand of the society as an organised whole. The work presentsconcrete measurements from practice and the indicators of thesituation regarding motor vehicles in Croatia. The EGO-TESThas been performed in Croatia according to the European Uniondirectives; first on the vehicles with petrol engines. Now, it isstarting to be applied on the vehicles with Diesel engines as well.Compliance with the EGO TEST regarding motor vehicles inCroatia will take into consideration the guidelines provided bythe European Union and thus reduce the harm from exhaustgases and noise pollution, and increase the possibility of usingmotor vehicles in order to reduce the danger and increase thesafety on the roads by excluding old vehicles from traffic.

Purpose of Quality Plan - arrangement of all necessary tests or inspections as far as possible filted to certain components or systems. Subject of Quality Plan - precise determination of tests or inspections and - according to the actual safety significance - the certificates to be done. Disposition of Quality Plan - accommodation of tests to the actual state of fabrication. Application of Quality Plan - to any component or system that is regarded. Supervision of Employment - by authorized personnel of manufacturer, customer or authority providing exact employment of quality plan. Overservance of Instructions - certificates given by authorized personnel. (orig./RW)

The main goal of the TopicalWorking Group on MIMO OTAis to gather all the relevant research across theWorking Groups in the IC1004Action for backingup choices to be made in standardisation on technologies for OTA testing of multi-antenna devices.As no standards are conceived in European cooperation....... The targeted application of MIMO OTA in standardisation is the conformance testing cycle, currently targeting RF performance only and not production testing. In this Chapter, contributions over the project duration are documented and resumed in a coherent way....

For over a year we have been advocating the development of a hardened or ruggedized version of Diamond which will be suitable for sequential detonation of multiple explosives in one emplacement hole. A Plowshare-sponsored device development test, named `Yacht` is proposed for execution in Area 15 at the Nevada Test Site [NTS] in late September 1972. The test is designed to evaluate the ability of a ruggedized Diamond-type explosive assembly to withstand the effects of an adjacent nuclear detonation in the same emplacement hole and then be sequentially fired. The objectives and experimental plan for this concept is provided.

Full Text Available Accelerated corrosion testing is indispensable for material selection, quality control and both initial and residual life time prediction for bare and painted metallic, polymeric, adhesive and other materials in atmospheric exposure conditions. The best known Neutral Salt Spray (NSS test provides unrealistic conditions and poor correlation to exposures in atmosphere. Modern cyclic accelerated corrosion tests include intermittent salt spray, wet and dry phases and eventually other technical phases. They are able to predict the material performance in service more correctly as documented on several examples. The use of NSS should thus be restricted for quality control.